Thione esters as substrates for the stereoselective alkylation of model compounds of nonactic acids

FULL PAPER

DOI: 10.1002/ejoc.200901513

Thione Esters as Substrates for the Stereoselective Alkylation of Model

Compounds of Nonactic Acids

François Loiseau,^[a][‡]Inga Kholod,^[a]and Reinhard Neier*^[a]

Keywords: Heterocycles / Diastereoselectivity / Retro reactions / Alkylation

The naturally occurring macrotetrolide antibiotic nonactin is

used in ammonium ion selective electrodes. To increase the

lifetime of nonactin in the semipermeable membrane of these

sensors we have developed methods for the introduction of

hydrophobic side-chains. Simple model compounds for non-

actic acid such as 5 and 7 were synthesised. Maintaining the

cis arrangement of the substituents in the 2,5-disubstituted

tetrahydrofurans proved to be difficult. Three different routes

were studied. The enolates obtained by treatment with

NaHMDS or KHMDS could be alkylated with benzyl or allyl

iodide as electrophiles. Under these conditions a cis/trans

isomerisation of the substituents on the tetrahydrofuran ring

occurred. A multistep methodology was developed as a syn-

thetic alternative. The sequence consisted of a selective

retro-Michael reaction, a 5-exo-tet iodocyclisation and a radi-

cal substitution. The products obtained by the two methodol-

ogies could be correlated, and thereby a tentative assign-

ment of the relative configurations could be achieved. In the

third route the thione ester 18 was deprotonated with tBuOK.

At temperatures below –78 °C, the enolate maintained the

cis configuration of the substituents at the tetrahydrofuran

ring. The alkylated product 12 could be isolated with a satis-

factory cis/trans ratio of 85:15. The model compound 12 could

be successfully transformed into more hydrophobic deriva-

tives by using either the Heck coupling or the cross-coupling

metathesis transformation.

progress, tricky separations of stereoisomers have to be per-

formed in all reported syntheses. Six total syntheses of the

macrotetrolide 1 have been described in the literature,^[6–11]

but isolation of the natural product from fermentation is

still the most efficient way to obtain 1.^[12]Major difficulties

are encountered during the synthesis of enantiopure (+)-

and (–)-nonactic acids (2) and during the assembly process.

Racemic nonactic acid can be resolved on a gram scale by

using mandelic acid derivatives^[13–15]or Rhodococcus eryth-

ropolis.^[12]Nonactin (1) is expensive and available in gram

quantities only, and therefore structurally simpler ionoph-

ores, like depsipeptides^[16]or tripodants,^[17]have been tested

as selective ionophores for the transport of ammonium

ions. However, nonactin (1) is still used commercially as the

standard ammonium-selective ionophore.

Introduction

Nonactin (1), an ionophore isolated from Streptomyces

shows interesting antibiotic properties. The macrotetrolide

1 selectively mediates ammonium and potassium transport

through lipophilic natural and artificial membranes,^[1]and

it is used as an additive in semipermeable membranes in

ammonium sensors.^[2]To increase the lifetime of this addi-

tive in the semipermeable membranes more lipophilic deriv-

atives of the natural macrotetrolide 1 are needed. We report

our efforts to modify model compounds of nonactic acid

(2) with the goal of introducing lipophilic side-chains at the

α-position to the carboxylic acid. First described in 1955,^[3]

1 is the smallest homologue of the nactin family. Nonactin

(1), an achiral meso compound, is composed of four consti-

tutionally identical chiral nonactic acid (2) molecules (Fig-

ure 1). Two molecules of (+)-2 are condensed with two mo-

lecules of (–)-2 in an alternating (+)(–)(+)(–) sequence,

which confers the unusual S₄symmetry on nonactin (1).

About 30 syntheses of nonactic acid and its derivatives have

been reported.^[4]Nonactic acid was considered to be a good

model structure for measuring the progress of modern syn-

thetic methodologies.^[5]However, despite the impressive

[a] Department of Chemistry, University of Neuchatel,

Avenue Bellevaux 51, 2000 Neuchatel, Switzerland

Fax: +41-32-718-25-11

E-mail: Reinhard.Neier@UniNE.ch

[‡] Current address: Lonza AG, R&D PD 2, 3930 Visp,

Switzerland

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.200901513.

Figure 1. Structures of nonactin (1) and (+)-nonactic acid (2).

4642

Alkylation of Model Compounds of Nonactic Acids

Scheme 1. Reported cis/trans epimerisation induced by the retro-Michael reaction of the ester enolate.^[26,27]

The lipophilicity of the ionophores used in sensors is the transesterification so that mixtures of methyl and ethyl

crucial factor determining the lifetime of ammonium-sensi- esters were obtained. Use of ethanol as solvent for the

tive electrodes using nonactin (1).^[18]We have recently re- second hydrogenation slowed reaction too much so that the

ported short and scalable routes to generate 2,5-disubsti- transformation became inefficient.

tuted furans and tetrahydrofurans, analogues of nonactic

acid.^[4,5d,19,20]We planned to introduce one to four lipo-

philic chains into nonactin to increase its lifetime in the

membranes. The cis arrangement of the substituents on the

tetrahydrofuran rings must be maintained during function-

alisation to preserve the capacity of optimal binding of the

cations.^[21–23]We report herein a method for diastereoselec-

tively introducing lipophilic side-chains (Figure 2) at the α-

position of the ester function of our model compounds

avoiding the undesired retro-Michael reaction.

Scheme 2. Catalytic hydrogenation of the furans 3 and 4.

Figure 2. Goal of our studies: to increase the lipophilicity of the

nonactin model compounds by alkylation.

In the end, differences in their reactivities were used for

their separation. Treatment of the mixtures of tetra-

Deprotonating the α-position of esters of this type in- hydrofuran and furylidene with KOH in the solvent mixture

duces cis/trans epimerisation at the tetrahydrofuran ring by water/THF (1:1) at reflux^[28,31]led to the exclusive saponifi-

an intramolecular retro-Michael reaction/recyclisation se- cation of 5 and 7, the furylidenes 6 and 8 remaining un-

quence (see Scheme 1).^[24,25]The only method reported in changed due to resonance stabilisation (Scheme 3). The ac-

the literature to maintain the cis arrangement blocks the ids were easily separated by silica gel chromatography. The

epimerisation by intramolecular lactone formation.^[26,27]

furylidenes 6 and 8 were obtained in pure form and could

be fully characterised. The ratio of the diastereoisomers re-

mained unchanged during saponification. This observation

is compatible with the assumption that no epimerisation of

the chiral centre at the α-position of the ester had oc-

curred.^[24]

Results and Discussion

Synthesis and Structure Assignment of the Model

Compounds

We attempted the introduction of lipophilic side-chains

by using the two model compounds 5 and 7. The molecules

5 and 7 preserve the essential features of nonactic acid, es-

pecially the crucial relative configuration of the two side-

chains on the tetrahydrofuran ring. Compounds 5 and 7

were synthesised by catalytic hydrogenation of the two 2,5-

disubstituted furans 3 and 4, respectively, with rhodium on

alumina as catalyst (Scheme 2).^[5,28]During the catalytic re-

duction we obtained reproducibly 6 and 8 as minor, so far

unknown, side-products, which were difficult to separate

from the tetrahydrofurans 5 and 7.^[29,30]Different ap-

proaches to separating the side-products from the desired

products were tried. A second hydrogenation converted the

Scheme 3. Selective saponification of tetrahydrofurans 5 and 7 in

furylidenes into the tetahydrofurans but also led to partial the presence of furylidenes 6 and 8.

Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

4643

F. Loiseau, I. Kholod, R. Neier

FULL PAPER

Catalytic hydrogenation has been reported to yield Our group has previously reported that by working below

mainly the desired cis diastereoisomers.^[29,30]The cis isomer –110 °C using 2-methyltetrahydrofuran (2-Me-THF)/THF

of 5, obtained by catalytic reduction of the furan 3, could as the solvent mixture, a facile β-elimination can be avo-

be partially separated from the trans isomer by chromatog- ided.^[34,35]By applying these conditions a slightly higher

raphy using a silica gel column. NOESY experiments con- diastereotopic ratio (dr) but lower yield was obtained (En-

firmed the cis configuration of the major isomer of 5. Two try 2 in Table 1). This result does not allow an unequivocal

fractions were obtained by silica gel chromatography of the interpretation. For additional information, see the Support-

product 7 obtained by catalytic reduction of 4. Each frac- ing Information.

tion contained a cis diastereoisomer as the major compo-

nent and one of the trans diastereoisomers as an impurity.

The major, more polar diastereoisomer was saponified. The

Table 1. Attempts to alkylate 5 by using NaHMDS as base.

acid 10a crystallised from diethyl ether. Its relative configu-

ration was determined with the help of X-ray diffraction.^[28]

The relative configuration of 10a is cis/anti. (The cis/trans

nomenclature is used to indicate the relative configuration

of the side-chains on the five membered ring, whereas the

syn/anti nomenclature follows the definition given by Evans

et al. to characterise the relative configuration of aldol

products at the α- and β-positions of the ester;^[32]see also

the Supporting Information.) The other cis diastereoisomer

7b has therefore the relative configuration cis/syn

(Scheme 4).

Entry

T [°C]

Yield [%]

dr^[a]

1

2

–78

–115

55

38

55:45

75:25

[a] Ratio of diastereoisomers, according to ¹H NMR spectroscopy.

Not surprisingly the substituted compound 7 was con-

siderably less reactive than 5 under the same conditions.

The yield of 12 was below 10% in all our attempts (experi-

ments not reported). To obtain acceptable yields of product

the stronger base KHMDS had to be used, which afforded

enolates with more ionic character. In our first attempt, 12

was obtained in 16% yield together with 44% of the ring-

opened compound 14 (Entry 1, Table 2). Shorter deproton-

ation times increased the yield of 12 (Entries 2 and 3,

Table 2). In an effort to optimise the yield of compound 12,

we changed the solvent mixture from toluene/THF (En-

tries 1–3 in Table 2) to THF/2-Me-THF without success

(Entries 4–6, Table 2). The use of 2-methyl-THF enabled

the reaction mixture to be stirred at temperatures below

–87 °C. Lowering the temperature for the deprotonation

and alkylation reactions from –78 to –90 °C and finally to

–100 °C lowered the overall yield without improving signifi-

cantly the ratio between the furan-containing product and

the ring-opened products (Entries 4–6, Table 2; see also the

Supporting Information). The isolation of compounds 13

and 14 was compatible with a retro-Michael process. In

Scheme 4. Structures of the diastereoisomers of 7 obtained by cata-

lytic hydrogenation.

Alkylation Using Enolate Chemistry

Alkylation of the α-position of esters by enolate chemis- most of the reactions 13 is a minor product (exception: En-

try has been widely studied. We decided to study this chem- try 6, Table 2). The ratio of 13/14 may be determined from

istry despite the reports of β-elimination in reactions involv- the quenching reaction and not the transformation itself.

ing tetrahydrofuran-containing substrates. We started our The chemo- and stereoselectivity of the alkylation process

study by using the model compound 5. NaHMDS, which were not satisfactory under any of the conditions studied

is less aggregated than LDA,^[33]gave encouraging results in by us.

the solvent mixture THF/DMPU (Entry 1 in Table 1). Two

We were not able to separate the two diastereoisomers of

out of four possible stereoisomers were obtained. This re- 12 by standard silica gel chromatography.^[29]We therefore

sult is compatible with the assumption that either the ring decided to assign the relative configuration of 12 by chemi-

junction (cis/trans) or the chiral centre next to the ester cal correlation (see the Supporting Information). We com-

(α/β) is preserved or highly stereocontrolled during this pro- pared the products obtained by the alkylation of 7 with

cess. If the retro-Michael reaction can be avoided, the for- products obtained by reduction of the corresponding furan

mation of the two stereoisomers could only be due to the 24. This comparison allowed us to tentatively assign the

newly introduced R group at the α-position of the ester. relative configuration.

4644

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4642–4661

Alkylation of Model Compounds of Nonactic Acids

Table 2. Alkylation reactions of 7 with KHMDS as base.

Entry

1

T₁[°C]/t₁[h]

–78/1

Solvent mixture^[a]

T₂[°C]/t₂[h]

Product (yield [%])

toluene/THF (40:60)

–78 to –20/1.5

12 (16)

13 (Ͻ4)

14 (44)

12 (33)

13 (4)

14 (20)

12 (43)

13 (Ͻ4)

14 (37)

12 (26)

13 (Ͻ4)

14 (Ͻ32)

12 (26)

13 (6)

2

3

4

5

6

–78/0.5

–87/0.5

–90/0.5

–100/0.5

toluene/THF (40:60)

toluene/THF/2-Me-THF^[b](40:30:30)

THF/2-Me-THF (50:50)

–78 to –70/0.5

–87 to 20/0.75

–87/0.5

THF/2-Me-THF (50:50)

–90/0.5

14 (30)

12 (16)

13 (18)

14 (18)

THF/2-Me-THF (50:50)

–100/0.5

[a] 10% of DMPU unless indicated otherwise. [b] Without DMPU.

Ring-Opening/Ring-Closing Sequence for the Alkylation

Our results are compatible with the mechanistic hypothe-

sis that ring-opening (retro-Michael reaction) occurred un-

der all the conditions tested and that the ring-closed prod-

ucts 11, 12 and S-4 (see the Supporting Information) had

been formed by a ring-opening/ring-closing sequence. In

this context it is worth mentioning that the biosynthesis of

nonactin uses Michael addition to a linear α,β-unsaturated

ester to form selectively the tetrahydrofuran ring.^[36–40]We

decided to take advantage of this inherent reactivity and to

use the ring-opened products as intermediates in our quest

to obtain lipophilically substituted analogues of nonactic

acid. We developed a second method that proceeds via ring-

opened intermediates to try to ascertain the syn/anti relative

configuration of the two centres at the α- and β-positions

of the ester (Figure 3). The strategy involves a three-step

Figure 3. Retrosynthetic analysis for the synthesis of 12 via the α-

halogeno ester 15.

To perform the planned sequence we had to obtain the

sequence: a retro-Michael reaction, a 5-exo-iodocyclisation ring-opened compound 13 selectively by a retro-Michael re-

to introduce a halogen atom and a stereospecific radical action. By using NaHMDS as base up to 40% of the

substitution of the iodine atom by a radical chain reaction double bond migrated leading to a loss of conjugation as a

(Figure 3).

result of deprotonation of 13 by the sodium alkoxide. By

Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

4645

F. Loiseau, I. Kholod, R. Neier

FULL PAPER

using LiHMDS in THF, the ring-opened product 13 was tially two diastereoisomers of 12 was isolated. The lower

obtained without detectable double-bond migration. yield obtained in our case in comparison with the yields

In our hands, conversion and yield were low [maximum reported in the literature is no surprise because of the di-

yield 39%; Scheme 5, path (i)]. By using the stronger base minished reactivity of tertiary iodides.

KHMDS in THF, total conversion of 7 could be achieved,

but double-bond migration could not be avoided. To obtain

good yields of the ring-opened product 13 we had to add

TBSCl as an internal quenching reagent, which gave the

TBS-protected product 16.^[41]Deprotection of the alcohol

with TBAF in THF led to a considerable amount of oligo-

merisation and thereby to a relatively low yield for the total

conversion [Scheme 5, total yield of 52% of 13 over the two

steps (ii) and (iii)].

Scheme 7. Radical substitution with allyltributyltin.

We tentatively assigned the configurations of the dia-

stereoisomers of 12 obtained in this three-step sequence by

correlating the products obtained by radical substitution

with the products obtained by alkylation of the enolate. The

radical substitution reaction has been reported to yield

preferentially the trans/syn and cis/syn diastereoiso-

mers.^[46,47]Assigning the relative configurations of the prod-

ucts obtained by the radical substitution process (Scheme 7)

Scheme 5. Selective retro-Michael reaction.

based on the literature report is compatible with the chemi-

According to the reports of Bartlett and co- cal correlation.

workers,^[8,42,43]we planned to use oxidative iodocyclisation

for the stereoselective synthesis of 2,5-disubstituted tetra-

hydrofurans.^[44]The oxidative 5-exo-iodocyclisation^[45]of

γ,δ-unsaturated alcohols has been reported to afford a mix-

ture of cis/syn and trans/syn diastereoisomers. The literature

reports indicate that the trans diastereoisomers are slightly

favoured in the iodocyclisation of δ,γ-unsaturated alcohols

(Scheme 6).^[43]

Stereoselective Alkylation Using Thione-Enolate Chemistry

As the yields and the diastereoselectivities of the two pro-

cesses studied so far were not satisfactory, we decided to

study the behaviour of thione esters, which should be easier

to deprotonate and therefore less prone to the retro-Michael

reaction. By using Lawesson’s reagent [2,4-bis(4-methoxy-

phenyl)-1,3-dithia-2,4-diphosphetane

2,4-disulfide],^[48,49]

the yields of thione esters 17 and 18 were disappointingly

small, less than 10% (see the Supporting Information). The

thione esters 17 and 18 were partially degraded during silica

gel chromatography. Curphey^[50]reported that the reactivity

of P₄S₁₀can be increased considerably by using hexamethyl-

disiloxane (HMDO). The side-products generated by the

P₄S₁₀/HMDO system can be easily removed by appropriate

workup procedures. We applied the optimal conditions re-

ported by Curphey (0.25–0.33 mol of P₄S₁₀per mol of ester,

3–4 mol of HMDO) using aqueous K₂CO₃and acetone

in the workup (Table 3). The conversion of 7 reached a

Scheme 6. Oxidative iodocyclisation.

To achieve the radical substitution, we applied the excel- satisfying 70–75%. Purification by silica gel chromatog-

lent work of Guindon and co-workers (Scheme 7)^[46,47]who raphy was necessary to separate unreacted esters from the

described this reaction for

a monosubstituted tetra- corresponding thione esters.

hydrofuran. According to their report, the syn product is

Deprotonating the thione ester 17 with LDA in THF fol-

favoured in the absence of Lewis acids. By using allyltribut- lowed by Michael addition to cyclopentenone^[51]gave a

yltin in hexane at reflux with AIBN as radical initiator, a non-optimised yield of 52% of 19 as a 75:25 mixture of two

moderate but acceptable 66% yield of a mixture of essen- diastereoisomers (Scheme 8). The product was formed as a

4646

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4642–4661

Alkylation of Model Compounds of Nonactic Acids

Table 3. Thionation of the model compounds 5 and 7 with P₄S₁₀/HMDO.

Entry

R^[a]

Solvent

Time^[b][h]

Conv.^[a][%]

Product/yield [%]

[c]

1

2

3

4

5

6

H

toluene

o-xylene

acetonitrile

16

20

17

20

–

17/42^[b]

18/30^[b]

18/100^[d]

18/34^[b]

18/27^[b]

18/–^[c]

Me

70

75

60

15

1

[a] According to H NMR spectroscopy. [b] Isolated by chromatography. [c] Not determined. [d] Raw product obtained after workup.

result of a 1,4-addition of the enolate of the thione ester to –78 °C before the addition of the electrophile. The race-

the α,β-unsaturated ketone. The cis/trans ratio of the start- mates of two diastereoisomers were isolated by chromatog-

ing material 17 was 90:10. The cis/trans ratio of the reco- raphy in 56 and 3% yields, respectively. Applying the same

vered starting material 17 was 70:30 after chromatography. reaction conditions to the α-methylated thione ester 18 gave

This reduction of the cis/trans ratio can be attributed to the similar results. The racemates of two diastereoisomers were

occurrence of the retro-Michael reaction.

again isolated by chromatography, this time in 66 and 20%

yields, respectively. The chemistry using the enolates of the

thione esters proved to be robust giving good yields of the

alkylated products.

We modified the reported reaction conditions in the hope

of avoiding the retro-Michael elimination. By keeping the

enolate of the thione ester at –78 °C we still observed total

conversion, and the alkylated products could be isolated in

a reproducible 85% yield. Only two diastereoisomers were

obtained in a 90:10 ratio according to ¹H NMR spec-

Scheme 8. Alkylation of thione ester with cyclopentenone.

By treating the enolate obtained under the same condi- troscopy. The GC ratio was 87:13, which is in good agree-

tions with allyl iodide, 20 was obtained in 62% yield and ment with the NMR result. This observation is compatible

25% of 17 was recovered (Table 4). By using tBuOK as base with the hypothesis that the retro-Michael elimination can

under the reaction conditions reported,^[52]total conversion be avoided by keeping the enolate of the thione ester at

could be achieved. The enolate of the thione ester was gen- –78 °C during the whole transformation. The only side-

erated at –78 °C, warmed to –10 °C and cooled again to product present in the raw material was the excess allyl io-

Table 4. Alkylation of 17 and 18 with allyl iodide.

Entry

R

Base (equiv.)

Allyl-I (equiv.)

Conditions 1

Conditions 2^[a]

Yield [%]/ratio^[b]

1

2

3

4

H

LDA (1.2)

allyl-I (1.2)

tBuOK (1.3)

allyl-I (1.3)

tBuOK (1.3)

allyl-I (1.3)

tBuOK (1.6)

allyl-I (1.6)

–78 °C, 0.5 h

–78 °C to –10 °C, 0.5 h

–78 °C to 7 °C, 0.5 h

–78 °C, 0.5 h

–78 °C to –10 °C, 2 h

–78 °C to –10 °C, 1.5 h

–78 °C to –10 °C, 1.3 h

62/–^[c]

56/70:30

Me

66/65:35^[a]

85/90:10^[d]

[a] 20% of an additional fraction containing some impurities was isolated. The ratio between the diastereoisomers was not determined

1

for this fraction. [b] Ratio between the two diastereomeric pairs of enantiomers, according to H NMR spectroscopy. [c] cis/trans ratio

of 20 was not determined, and starting material 17 (25%) was recovered. [d] A quantitative yield was recovered before chromatography.

Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

4647

F. Loiseau, I. Kholod, R. Neier

FULL PAPER

dide. Drying of the crude product after workup removed conversion of thiocarbonyl groups into carbonyl groups in

the volatile allyl iodide and gave the product in quantitative the presence of double bonds. We therefore tested these

yield without chromatography.

conditions with compound 20. We obtained a drastically

If this methodology is to be applicable to nonactin (1) reduced yield of only 28% of 11. By using 21 as the sub-

the alkylation reaction has to be selective for the thione strate, 22 h were required to obtain total conversion. Elu-

ester in the presence of ester functions. We tested the reac- tion of the polar fractions from the chromatography col-

tion by using a 50:50 mixture of 18/7 (Table 5). The thione umn with AcOEt/MeOH showed the presence of uncharac-

ester should be more acidic than the ester, and selective terised polar compounds lacking the double bond. This is

transformation of the thione ester should be feasible.^[53]circumstantial evidence that m-CPBA attacked the double

With 1.05 equiv. of tBuOK, the formation of acrylate 13 bonds of 20 and 21. To avoid the problems of overoxidation

could not be completely avoided: 7.4% of 7 was trans- we tested the reagent trifluoroacetic anhydride (TFAA) in

formed into the ring-opened product 13, whereas 12.3% of the reaction with 18.^[57]The reaction was exothermic at the

thione ester 18 remained unreacted. By reducing the beginning. However, the conversion stopped after only

amount of tBuOK to 0.85 equiv., only 4.6% of acrylate 13 35%. Finally, tin derivatives like (Bu₃Sn)₂O and Bu₂SnO in

was formed. However, the conversion to thione ester 18 was dioxane at reflux^[58]afforded the best results for the trans-

also lower. The cis/trans ratios of the products 7, 18 and 21 formation of the thione esters into the ester function. Sev-

were still roughly 90:10. Therefore, selective transformation eral days were required to obtain total conversion of 21, as

of thione esters in the presence of “normal” esters is feas- indicated by GC–NMR.^[59]The unoptimised yield of 12

ible.

was 66% with (Bu₃Sn)₂O and 48% with Bu₂SnO. The ex-

cess of Bu₂SnO is easier to remove than the excess of

(Bu₃Sn)₂O, because the reaction mixture is heterogeneous.

Table 5. Allylation from a 50:50 mixture of 18/7.

Entry

tBuOK [equiv.]

7/18/13/21^[a]

1

2

1.05

0.85

46:12.3:7.4:34.3

32.3:32.6:4.6:30.5

Introduction of Hydrophobic Side-Chains by

Organometallic Coupling

[a] According to GC.

Having achieved the functionalisation α to the ester func-

We then studied the conversion of thione ester back to tion we decided to apply the Heck and metathesis^[60–63]re-

the ester function. Corsaro and Pistara reported in 1998 in actions to modify the terminal double bond of 12 and

their review^[54]many different reagents for the conversion thereby increase the lipophilicity of our model compounds.

of thiocarbonyl groups into carbonyl groups. We tested first

For the cross-metathesis reaction we used 1-(hex-5-en-

the behaviour of thione ester 17 against P(OMe)₃at 105 °C. yloxy)dodecane (23), prepared in one step by treating hex-

The ¹H NMR spectrum of the crude reaction mixture 5-en-1-ol (22) with 1-bromododecane under the conditions

showed complete loss of the compound (Table 6). The reported for the alkylation of hex-5-en-1-ol with bromo-

thione ester was then treated with [Fe(CO)₅] in toluene at nonane.^[64]Deprotonation of the alcohol 22 with NaH at

reflux.^[55]The maximum conversion never exceeded 70%. room temperature for 2 h followed by alkylation with 1-

By using m-CPBA total conversion of 17 could be achieved. bromododecane gave the product 23 in moderate yield

It has been reported that m-CPBA^[56]in CH₂Cl₂allows the (Table 7).

Table 6. Conversion of thione esters into their corresponding esters.

Entry

R

RЈ

Reagent

Conditions

Conv.^[a][%]

Yield^[b][%]

0

1

2

3

4

5

6

7

8

9

H

Me

H

Me

H

allyl

Me

H

allyl

P(OMe)₃

[Fe(CO)₅]

m-CPBA

TFAA

(Bu₃Sn)₂O

Bu₂SnO

105 °C

100

70

100

Ͻ90

90

Ͻ30

100

Ͼ95

[c]

toluene, 105 °C, 16 h

CH₂Cl₂, 25 °C, 2 h

CH₂Cl₂, 25 °C, 4 h

CH₂Cl₂, 20 °C, 22 h

CH₂Cl₂, 25 °C, 4 h

dioxane, reflux, 15 h

dioxane, reflux, 48 h

dioxane, reflux, 8 d^[d]

–

55

28

29

[c]

–

43

66

48

[a] According to ¹H NMR spectroscopy. [b] Isolated by chromatography. [c] Not determined. [d] Overall time for the two reactions

required to obtain total conversion.

4648

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4642–4661

Alkylation of Model Compounds of Nonactic Acids

Table 7. Synthesis of 1-(hex-5-enyloxy)dodecane (23).

Surprisingly, 12 was considerably less reactive than 24.

After 20 h in CH₂Cl₂, only 14% of 30 had undergone the

cross-metathesis reaction. We suppose that residual tin de-

rivatives from the previous step could be responsible for the

lower reactivity. Use of 1,2-dichloroethane and the addition

of further quantities of Grubbs I catalyst during the reac-

tion increased the yield to 46% for 30 and 42% for 29. The

large amount of catalyst needed also led to 10% of 31 and

13% of 32, products obtained by cross-coupling with the

benzylidene coming from the Grubbs catalyst (Scheme 9).

Entry

T [°C]

t₁[h]

t₂[h]

Yield [%]

1

2

3

20

50

0.25

2

20

3.5

20

23

40

47

1

According to H NMR analysis, the (E)/(Z) ratio is 75:25

for 30 and 29, whereas for 32 only the (E) diastereoisomer

1

could be detected in the H NMR spectrum.

For our model studies we tested only the Grubbs I cata-

lyst.^[63,65,66]Preliminary attempts at the cross-metathesis re-

action between the furan 24 and the olefin 22 afforded 25

in 81% yield (Table 8). The side-products formed by self-

coupling were isolated in variable yields:^[62]side-products

26 and 27 formed in minor quantities were not isolated.

Alkylation of 25 with 1-bromododecane under the condi-

tions developed for the synthesis of 23 gave low yields (not

reported). NMR analysis of the crude product obtained by

cross-metathesis between 23 and furan 24 indicated a good

transformation of the starting materials and the presence of

a high amount of the product 29. On reducing the excess

of 23 from 1.6 to 1.2 equiv., the product 28 could still be

isolated in an acceptable yield of 54%. The two homodi-

mers 29 (21%) and 27 (8%) were also isolated. Finally, 24

and 23 were allowed to react in equimolar amounts. The

homodimers 29 and 27 were isolated in 3 and 6% yields,

respectively. Full conversion of 24 could not be achieved

under these conditions. The ¹H NMR analysis showed that

the (E)/(Z) ratio for both 28 and 25 is 65:35.

Scheme 9. Cross-metathesis reaction of furan 12 and alkene 23.

Table 8. Cross-metathesis of furan 24.

Entry

Olefin [equiv.]

Self-coupling^[a]product/yield [%]

Conv. of 24 [%]

Product/ yield [%]

[b]

1

2

3

22 [1.6]

23 [1.2]

23 [1.0]

–

100

90^[a]

25/81

28/54^[a]

28/30^[c]

29/21;^[a]27/8^[c]

29/3;^[a]27/6^[c]

1

[a] According to H NMR spectroscopy. [b] Not determined. [c] Isolated by chromatography.

Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

4649

F. Loiseau, I. Kholod, R. Neier

FULL PAPER

Scheme 10. Heck coupling reaction of compound 24 with 33.

Scheme 11. Heck coupling reaction of compound 12 with 33.

We decided to test the Heck reaction as an alternative corresponding thione esters was achieved in moderate

method for introducing the hydrophilic side-chains. Mizo- yields. Use of the enolate generated from the thione ester

roki et al. reported the first case of a Heck reaction in has allowed the introduction of activated alkyl substituents

1971^[67]using MeOH as solvent at 120 °C. One year later at the α-position of the ester, creating a quaternary centre.

Heck and Nolley reported milder conditions.^[68]The so- This procedure avoids to a large extent the cis/trans iso-

called Heck coupling reaction has become one of the most merisation of the side-chains of the tetrahydrofuran ring.

efficient synthetic methodologies for coupling between ole- The products of the alkylation reactions were successfully

fins and aromatic halides.^[69]We decided to use 1-iodo-4- converted into the corresponding esters by using tin oxide

octadecyloxybenzene (33), synthesised from commercially derivatives. The relative configurations of the chiral centres

available 4-iodophenol and octadecyl iodide in a moderate were maintained during this process. Cross-metathesis as

58% yield after 24 h. We used the furan derivative 24 for well as Heck coupling could be successfully applied, intro-

the optimisation of the conditions.^[70,71]Complete transfor- ducing lipophilic side-chains in good to excellent yields. The

mation could be achieved within 48 h (Scheme 10). The Heck reaction gave slightly better results than the cross-

combined overall yield of 34a and 34b was more than 90%. metathesis reaction, forming smaller amounts of side-

In the case of compound 12, 84 h were required to products.

achieve total consumption (Scheme 11). The overall com-

bined yield of 35a and 35b was only 60%. Small amounts

Experimental Section

of residual tin derivatives from the previous step might be

responsible for the reduced reactivity. A mixture of two re-

gioisomers was isolated in a 90:10 ratio in both reactions.

The major isomers 34a and 35a have the relative configura-

tion (E).

General: All chemicals were used as received unless otherwise

noted. Reagent-grade solvents were distilled prior to use. All re-

ported NMR spectra were recorded in CDCl₃(Cambridge Isotope

Laboratories) at 298 K either with a Bruker Avance 400 spectrome-

ter at 400 (¹H) and 100 MHz (¹³C) or with a Varian Gemini XL-

200 spectrometer at 200 (¹H) and 50 MHz (¹³C). Chemical shifts

are reported as δ values relative to TMS, defined as δ = 0.00 ppm

(¹H) or δ = 0.0 ppm (¹³C) and are referenced to the residual proton-

ated NMR solvent, defined as δ = 7.264 ppm (¹H) or δ = 77.00 ppm

Conclusions

Simple analogues of ethyl nonactate 5 and 7 have been

successfully prepared. These model compounds were used (¹³C). In the case of two isomers, 1,2,3-labelling was applied to the

major isomer and 1Ј,2Ј,3Ј-labelling was used to refer to the minor

isomer. Infrared spectra were obtained with a Perkin–Elmer Spec-

trum One version B FT-IR unit by using KBr pressed films or

KBr disks. Mass spectra were obtained with a ThermoFinnigan

PolarisQ instrument by EI (70 eV) or with a ThermoFinnigan LCQ

instrument by ESI or APCI. HRMS were recorded with a Bruker

BioAPEX II Daltonics instrument. Flash column chromatography

was performed on silica gel (Kieselgel 60, 230–400 mesh ASTM).

TLC analyses were performed on silica gel plates (0.2 mm) 60 F₂₅₄

(Merck). Detection was first achieved by UV light (254 nm) and

to develop reaction conditions suitable for the diastereo-

selective introduction of hydrophobic side-chains at the α-

position of the ester functionality (Schemes 10 and 11).

With NaHMDS and KHMDS as bases, direct alkylation

was possible by using enolate chemistry. Under these reac-

tion conditions, partial isomerisation of the crucial relative

configuration of the side-chains on the tetrahydrofuran ring

occurred. The relative configurations of the new com-

pounds were tentatively assigned by chemical correlation.

Transformation of the model compounds 5 and 7 into the then by charring with a basic aqueous solution of KMnO₄. Prepar-

4650 Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

Alkylation of Model Compounds of Nonactic Acids

ative thin-layer chromatography was performed on silica gel

plates (20ϫ20 cm) 60 F₂₅₄(Merck). Isomeric ratios were deter-

mined by gas chromatography (Agilent 6850 Series chromatograph)

with

a

high-resolution gas-chromatograph HP-5 column

(30 mϫ0.32 mmϫ0.25 µm), and the configurations were assigned

by comparison of the retention times with reported values. The

following temperature programs were employed: (1) 50 °C/

perature under a pressure of 3.9 atm for 16 h. The reaction mixture

was filtered through a mixture of Celite/silica gel (2:1) and washed

with Et₂O. Removal of the solvents by rotary evaporation afforded

colourless oil 7 as a complex mixture of four pairs of enantiomers.

The two pairs of cis-disubstituted major enantiomers (7a and 7b)

were separated in a 60:40 ratio by chromatography in order to be

characterised. However, each of them also contained one of two

pairs of trans-disubstituted minor enantiomers (7c and 7d). When

8 was formed in considerable quantity, a second hydrogenation was

carried out. R_f(hexane/EtOAc, 90:10) = 0.14 (cis isomer 7a), 0.21

(cis isomer 7b). GC (temp. progr. 1): t_R= 10.08 (isomer 1, cis-7b,

37%), 10.33 (isomer 1, trans-7c, 4%), 10.83 (isomer 2, cis-7a, 54%),

10.96 min (isomer 2, trans-7d, 5%). GC (temp. progr. 2): t_R= 5.08

(isomer 1, cis-7b, 39%), 5.12 (isomer 1, trans-7c, 4%), 5.24 (isomer

2, cis-7a, 55%), 5.40 min (isomer 2, trans-7d, 2%). IR (KBr film):

3 °Cmin^–1/110 °C

(0 min)/20 °Cmin^–1/250 °C;

(2)

50 °C/

20 °Cmin^–1/140 °C (1 min)/5 °Cmin^–1/250 °C (10 min); (3) 30 °C/

20 °Cmin^–1/110 °C (0 min)/10 °Cmin^–1/250 °C. GC–MS analyses

were performed with a ThermoFinnigan PolarisQ instrument,

equipped with a Trace GC gas chromatograph and a PolarisQ mass

spectrometer. The following temperature program was employed:

60 °C (1 min)/10 °Cmin^–1/250 °C (60 min).

General Procedure for Catalytic Hydrogenation

Ethyl 2-(5-Methyltetrahydrofuran-2-yl)acetate (5): Methanol

(15 mL) and furan 3 (400 mg, 2.38 mmol) were added to rhodium

on activated alumina (50 mg, 0.024 mmol) introduced into a glass

hydrogenation bottle under argon. The resulting mixture was hy-

drogenated in a shaker-type hydrogenation apparatus at room tem-

perature under a pressure of 3.6 atm for 12 h. The reaction mixture

was filtered through a mixture of Celite/silica gel (2:1) and washed

with Et₂O. Removal of the solvents by rotary evaporation afforded

a yellow oil. This product was purified by chromatography on silica

gel (hexane/EtOAc, 9:1) to give a colourless oil 5 as a mixture of

two isomers in an 85:15 ratio (¹H NMR integral estimation,

NOESY correlation 1-H,4-H) in 77% overall yield (316 mg,

1.83 mmol). Sometimes traces of ethyl 2-[5-methyldihydrofuran-

2(3H)-ylidene]acetate (6) were observed. Two signal sets were ob-

served in the ¹H NMR spectrum (ratio 85:15), which were assigned

to the cis (major) and trans (minor) isomers. The signals of the

ν = 2975 (s), 2939 (m), 2875 (m), 1736 (vs), 1631 (vw), 1461 (m),

˜

1377 (s), 1330 (w), 1257 (s), 1179 (s), 1093 (s), 1057 (m), 1024 (w),

950 (w), 906 (w), 862 (vw) cm^–1. cis-7a: ¹H NMR (400 MHz,

2

3

CDCl₃, 298 K): δ = 4.16 (dq, J_H7a,H7b= 10.8, J_H7a,H8= 7.1 Hz,

2

3

1 H, 7a-H), 4.15 (dq, J_H7b,H7a= 10.8, J_H7b,H8= 7.1 Hz, 1 H, 7b-

3

H), 4.00 (q, J_H1,H5

=

³J_H1,H2,obs.≈ 7.2 Hz, 1 H, 1-H), 3.95

3 3

3

(≈dquint, J_H4,H3a,obs.= 7.5, J_H4,H3b,obs.= J_H4,H9≈ 6.1 Hz, 1 H,

4-H), 2.55 (≈quint, ³J_H5,H1= ³J_H5,H10,obs.≈ 7.2 Hz, 1 H, 5-H), 2.02–

1.86 (m, 2 H, 3a-H, 2a-H), 1.68–1.57 (m, 1 H, 2b-H), 1.45–1.35

(m, 1 H, 3b-H), 1.24 (t, ³J_H8,H7= 7.1 Hz, 3 H, 8-H), 1.18 (d, ³J_H9,H4

3

= 6.1 Hz, 3 H, 9-H), 1.10 (d, J_H10,H5= 7.2 Hz, 3 H, 10-H) ppm.

¹³C NMR (100 MHz, CDCl₃, 298 K): δ = 174.9 (C-6), 80.3 (C-1),

75.5 (C-4), 60.2 (C-7), 45.2 (C-5), 32.6 (C-3), 28.5 (C-2), 21.2 (C-

9), 14.1 (C-8), 13.1 (C-10) ppm. cis-7b: ¹H NMR (400 MHz,

1

trans isomer are hidden by those of the cis isomer in the H NMR

spectrum; however, they can be assigned in the ¹³C NMR spectrum.

3

CDCl₃, 298 K): δ = 4.13 (q, J_H7,H8= 7.1 Hz, 2 H, 7-H), 4.01–3.91

(m, 2 H, 1-H, 4-H), 2.55 (≈quint, J_H5,H1,obs.

R_f(hexane/EtOAc, 90:10) = 0.40. GC (temp. progr. 1): t_R= 9.08

3

= ≈

³J_H5,H10,obs.

(cis-5a, 84%), 9.33 min (trans-5b, 16%). IR (KBr film): ν = 2975

˜

7.1 Hz, 5-H), 1.99–1.93 (m, 2 H, 3a-H, 2a-H), 1.74–1.65 (m, 1 H,

(m), 2875 (w), 1736 (vs), 1463 (w), 1447 (w), 1377 (m), 1279 (m),

1300 (m), 1202 (s), 1175 (s), 1086 (s), 1031 (s), 936 (vw), 881 (vw),

853 (vw) cm^–1. ¹H NMR (400 MHz, CDCl₃, 298 K): δ = 4.37

(≈quint, ³J_H1,H2= ³J_H1,H5= 6.7 Hz, 1 H, 1Ј-H), 4.24 (quint, ³J_H1,H2

2b-H), 1.46–1.41 (m, 1 H, 3b-H), 1.24 (t, ³J_H8,H7= 7.1 Hz, 3 H, 8-

3

H), 1.22 (d, J_H10,H5= 7.0 Hz, 3 H, 10-H), 1.19 (d, J_H9,H4,obs.

=

6.1 Hz, 3 H, 9-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K): δ =

174.7 (C-6), 80.3 (C-1), 75.5 (C-4), 60.2 (C-7), 45.3 (C-5), 32.7

(C-3), 29.3 (C-2), 21.2 (C-9), 14.2 (C-8), 14.0 (C-10) ppm. MS

(APCI⁺): m/z (%) = 187.0 (100) [M + H]⁺. HRMS: calcd. for

[C₁₀H₁₈O₃Na]⁺209.11481; found 209.11464.

3

= J_H1,H5= 6.7 Hz, 1 H, 1-H), 4.12 (q, J_H7,H8= 7.1 Hz, 4 H, 7-

3

H, 7Ј-H), 4.11–4.06 (m, 1 H, 4Ј-H), 3.93 (≈dquint, J_{H4,H3a or}3b-

3

H = 7.5, J_{H4,H3b or}3a-H = J_H4,H9= 6.2 Hz, 1 H, 4-H), 2.62 (dd,

²J_H5b,H5a= 15.2, ³J_H5b,H1= 6.7 Hz, 1 H, 5b-H), 2.56 (dd, ²J_H5bЈ,H5aЈ

= 14.9, J_H5bЈ,H1Ј= 7.0 Hz, 1 H, 5aЈ-H), 2.47 (dd, ²J_H5a,H5b= 15.2,

3

³J_H5a,H1= 6.6 Hz, 1 H, 5a-H), 2.41 (dd, ²J_H5aЈ,H5bЈ= 14.9, ³J_H5aЈ,H1Ј

= 6.4 Hz, 1 H, 5aЈ-H), 2.12–1.96 (m, 4 H, 2a-H, 2aЈ-H, 3a-H, 3aЈ-

H), 1.74–1.55 (m, 2 H, 2b-H, 2bЈ-H), 1.50–1.38 (m, 2 H, 3b-H, 3bЈ-

3

H), 1.22 (t, J_H8,H7= J_H8Ј,H7Ј= 7.1 Hz, 6 H, 8-H, 8Ј-H), 1.19 (d,

³J_H9,H4= 6.2 Hz, 3 H, 9-H), 1.19 (d, J_H9Ј,H4Ј= 6.2 Hz, 3 H, 9Ј-H)

3

ppm. cis-5a: ¹³C NMR (100 MHz, CDCl₃, 298 K): δ = 171.3 (C-

6), 75.6 (C-4), 75.3 (C-1), 60.3 (C-7), 41.2 (C-5), 32.6 (C-3), 31.2

(C-2), 21.4 (C-9), 14.2 (C-8) ppm. trans-5b: ¹³C NMR (100 MHz,

CDCl₃, 298 K): δ = 171.3 (C-6Ј), 74.9 (C-4Ј), 74.8 (C-1Ј), 60.3

(C-7Ј), 41.0 (C-5Ј), 33.7 (C-3Ј), 32.0 (C-2Ј), 21.2 (C-9Ј), 14.2

(C-8Ј) ppm. HRMS: calcd. for [C₉H₁₆O₃Na]⁺195.09917; found

195.09973.

Ethyl (E)-2-[5-Methyldihydrofuran-2(3H)-ylidene]propanoate (8):

The ester 8 was formed as a byproduct according to the procedure

given for compound 7. To isolate this compound, a mixture

(470 mg, 7/8, 90:10) of 7 (422 mg, 2.27 mmol) and 8 (48 mg,

0.26 mmol) was dissolved in THF (30 mL) at 20 °C, and then a

solution of KOH (472 mg, 8.4 mmol) in distilled water (30 mL) was

added portionwise. The reaction mixture was heated at reflux for

16 h with stirring. THF was removed in a rotary evaporator, and

Ethyl 2-(5-Methyltetrahydrofuran-2-yl)propanoate (7): Methanol

(30 mL) and furan 4 (1.00 g, 5.49 mmol) were added to rhodium the resulting residue was treated with an aqueous 32% solution of

on activated alumina (90 mg, 0.045 mmol) introduced into a glass

hydrogenation bottle under argon. The resulting mixture was hy-

drogenated in a shaker-type hydrogenation apparatus at room tem-

HCl (1.17 mL, 10.4 mmol). The reaction mixture was extracted

with Et₂O (4ϫ30 mL), and the combined organic layers were

washed with brine (40 mL), dried with anhydrous MgSO₄and fil-

Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

4651

F. Loiseau, I. Kholod, R. Neier

FULL PAPER

tered. The solvent was evaporated to give a yellow oil, which was

purified by flash chromatography on silica gel (hexane/EtOAc,

90:10 and then EtOAc/MeOH, 95:5) to give the non-saponified es-

ter 8 (29 mg, 0.16 mmol) and the acid 9 (310 mg, 1.96 mmol, 86%).

(vs), 1643 (w), 1444 (w), 1376 (m), 1299 (vw), 1268 (w), 1176 (s),

1132 (w), 1093 (s), 1027 (m), 914 (w), 855 (vw) cm^–1. ¹H NMR

3

(400 MHz, CDCl₃, 298 K): δ = 5.77 (dddd, J_H11,H12b= 17.1,

³J_H11,H12a= 10.1, ³J_{H11,H10a,obs.}= 7.1, ³J_H11,H10b= 6.8 Hz, 1 H, 11-

1

3

8: R_f(hexane/EtOAc, 90:10) = 0.27. H NMR (400 MHz, CDCl₃,

H), 5.76 (m, 1 H, 11Ј-H), 5.05 (≈dq, J_H12b,H11

=

³J_H12bЈ,H11Ј

=

3

298 K): δ = 4.50 (dquint, J_H4,H3a= 8.1, J_H4,H3b

=

³J_H4,H9

=

17.1, ²J_H12b,H12a= ²J_{H12bЈ,H12aЈ}= ³J_H12b,H10= ³J_H12bЈ,H10Ј= 1.5 Hz,

6.2 Hz, 1 H, 4-H), 4.17 (q, ³J_H7,H8= 7.1 Hz, 2 H, 7-H), 3.26 (dddq,

2 H, 12b-H, 12bЈ-H), 4.98 (dd, J_H12a,H11

=

³J_H12aЈ,H11Ј= 10.1,

3

²J_H2b,H2a= 18.3, J_H2b,H3a= 9.0, J_H2b,H3b= 4.1, J_H2b,H10

=

≈

²J_H12a,H12b= J_{H12aЈ,H12bЈ,obs.}= 1.0 Hz, 2 H, 12a-H, 12aЈ-H), 4.18

3

5

2

3

2

3

1.3 Hz, 1 H, 2b-H), 2.94 (≈dtq, J_H2a,H2b= 18.3, J_H2a,H3a

(dq, J_H7a,H7b= 10.5, J_H7a,H8= 7.1 Hz, 1 H, 7a-H), 4.17 (dq,

³J_H2a,H3b≈ 9.0, J_H2a,H10= 1.7 Hz, 1 H, 2a-H), 2.20 (dddd, ²J_H7aЈ,H7bЈ= 10.5, J_H7aЈ,H8Ј= 7.1 Hz, 1 H, 7a^Ј-H), 4.15 (m, 1 H,

5

3

²J_H3b,H3a= 12.3, ³J_H3b,H2a= 9.0, ³J_H3b,H4= 8.1, ³J_H3b,H2b= 4.1 Hz,

1Ј-H), 4.14 (dq, J_H7b,H7a= 10.5, J_H7b,H8= 7.1 Hz, 1 H, 7b-H),

2

3

5

2

3

1 H, 3b-H), 1.80 (≈t, J_H10,H2,obs.= 1.5 Hz, 3 H, 10-H), 1.66 (dtd,

4.11 (dq, J_H7bЈ,H7aЈ= 10.5, J_H7bЈ,H8Ј= 7.1 Hz, 1 H, 7b^Ј-H), 4.08

(≈dm, J_{H4Ј,H3aЈ or 3bЈ-H,obs.}= 8.2, J_{H4Ј,H3bЈ or 3aЈ-H}

²J_H3a,H3b= 12.3, J_H3a,H2a= J_H3a,H2b= 9.0, J_H3a,H4= 8.1 Hz, 1

=

³J_H4Ј,H9Ј

=

3

H, 3a-H), 1.37 (d, J_H9,H4= 6.2 Hz, 3 H, 9-H), 1.27 (t, J_H8,H7

=

6.1 Hz, 1 H, 4Ј-H), 4.01 (≈q, J_H1,H2a,obs.=

³J_H1,H2b,obs.

7.1 Hz, 3 H, 8-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K): δ =

³J_H1,H5,obs.= 7.3 Hz, 1 H, 1-H), 3.97 (≈dquint, J_H4,H3a= 7.5,

3

170.7, 169.9 (C-1, C-6), 97.5 (C-5), 79.9 (C-4), 59.8 (C-7), 32.1 (C-

³J_H4,H3b

=

³J_H4,H9= 6.1 Hz, 1 H, 4-H), 2.49 (ddd, J_H5,H10a

=

3), 31.9 (C-2), 21.0 (C-9), 14.9 (C-8), 11.7 (C-10) ppm. MS (EI, ³J_{H5Ј,H10aЈ,obs.}= 10.2, J_H5,H1,obs.= J_{H5Ј,HЈ1,obs.}= 8.0, J_H5,H10b

3

70 eV): m/z (%) = 185.32 (100) [M + H]⁺, 84.32 (78) [M]⁺, 139.30

(58) [M – H – CO₂]⁺, 138.30 (58) [M – 46]⁺, 111.30 (27) [M – H –

CO₂Et]⁺, 102.23 (65) [M – 83]⁺.

³J_{H5Ј,H10bЈ,obs.}= 4.3 Hz, 2 H, 5-H, 5Ј-H), 2.38–2.30 (m, 2 H, 10a-

H, 10aЈ-H), 2.28–2.15 (m, 2 H, 10b-H, 10bЈ-H), 2.08–1.91 (m, 4 H,

2a-H, 2aЈ-H, 3a-H, 3aЈ-H), 1.74–1.60 (m, 2 H, 2b-H, 2bЈ-H), 1.50–

1.38 (m, 2 H, 3b-H, 3bЈ-H), 1.24 (t, ³J_H8Ј,H7Ј= 7.1 Hz, 3 H, 8Ј-H),

3

1.24 (t, J_H8,H7= 7.1 Hz, 3 H, 8-H), 1.19 (d, J_H9,H4= 6.0 Hz, 3

H, 9-H), 1.18 (d, J_H9Ј,H4Ј= 6.1 Hz, 3 H, 9Ј-H) ppm. ¹³C NMR

3

(100 MHz, CDCl₃, 298 K): δ = 173.6 (C-6, C-6Ј), 135.1 (C-11, C-

11Ј), 116.6 (C-12, C-12Ј), 79.7, 79.1 (C-1, C-1Ј), 75.5, 75.0 (C-4, C-

4Ј), 60.2 (C-7, C-7Ј), 51.5, 51.3 (C-5, C-5Ј), 33.6, 33.2 (C-3, C-3Ј),

33.0, 32.5 (C-10, C-10Ј), 30.1, 29.1 (C-2, C-2Ј), 21.3, 21.1 (C-9, C-

9Ј), 14.3 (C-8, C-8Ј) ppm. MS (ESI⁺): m/z (%) = 213.31 (100)

[M + H]⁺, 171.31 (20) [M – 41]⁺= [M – allyl]⁺, 125.26 (30) [M –

87]⁺= [M – allyl – EtOH]⁺, 85.25 (50) [M – 125]⁺, 67.23 (42) [M –

145]⁺. HRMS: calcd. for [C₁₂H₂₂O₃Na]⁺235.13047; found

235.13003.

Ethyl 2-(5-Methyltetrahydrofuran-2-yl)pent-4-enoate (11). Method

A: At –78 °C, NaHMDS (1 , 3.8 mL, 3.8 mmol) was added to a

cooled mixture of dry THF (7 mL) and DMPU (1 mL) at –75 °C

under argon. A solution of 5 (500 mg, 2.9 mmol) in dry THF

(5 mL) was added dropwise over a period of 15 min to the resulting

mixture at –78 °C. The reaction mixture was stirred for 1.66 h, and

then a solution of allyl iodide (2 mL, 21.9 mmol) in dry THF

(2 mL) was added dropwise over a period of 10 min. Stirring was

continued at –78 °C for 1.5 h, and then the resulting mixture was

warmed to –50 °C over a period of 0.5 h and diluted with saturated

aqueous NH₄Cl solution (7.5 mL), water (1 mL) and Et₂O (20 mL).

The layers were separated, and the aqueous layer was extracted

with Et₂O (2ϫ20 mL). The combined organic layers were washed

with brine (20 mL) and dried with anhydrous MgSO₄. After fil-

tration, the solvent was removed in vacuo, and the residue was

purified by chromatography on silica gel (hexane/EtOAc, 90:10) to

give compound 11 (340 mg, 1.6 mmol, 55%) as a mixture of two

pairs of enantiomers in a ratio of 55:45 ratio. Method B: At

–115 °C, DMPU (1.2 mL) in dry THF (2 mL) was added to a co-

Ethyl 2-Methyl-2-(5-methyltetrahydrofuran-2-yl)pent-4-enoate (12).

Method A: KHMDS (1.05 g, 5.23 mmol) was added to a cooled

mixture of dry THF (7.5 mL), dry 2-Me-THF (7.5 mL) and

DMPU (1.5 mL) at –87 °C under argon. A solution of 7 (0.76 g,

4.03 mmol) in a mixture of dry THF (1.5 mL) and dry 2-Me-THF

(1.5 mL) was added dropwise to the resulting mixture. The reaction

oled mixture of dry 2-Me-THF (3 mL) and NaHMDS (1 , mixture was stirred for 45 min, and then a solution of allyl iodide

3.8 mL, 3.8 mmol) at –60 °C under argon. A solution of 5 (500 mg,

2.9 mmol) in a mixture of dry THF (2 mL) and dry 2-Me-THF

(1 mL) was added dropwise over a period of 25 min to the resulting

mixture at –115 °C. The reaction mixture was stirred for 2 h, and

then a solution of allyl iodide (2.65 mL, 29 mmol) was added drop-

wise over a period of 17 min. Stirring was continued at –115 °C for

1.25 h, and then the resulting mixture was warmed to –40 °C over

a period of 0.75 h and diluted with saturated aqueous NH₄Cl solu-

tion (7.5 mL), water (1 mL) and Et₂O (20 mL). The layers were

separated, and the aqueous layer was extracted with Et₂O

(2ϫ20 mL). The combined organic layers were washed with brine

(20 mL) and dried with anhydrous MgSO₄. After filtration, the sol-

vent was removed in vacuo, and the residue was purified by

chromatography on silica gel (hexane/EtOAc, 90:10) to give com-

pound 11 (227 mg, 1.06 mmol, 38%) as a mixture of two pairs of

enantiomers in a ratio of 75:25. R_f(hexane/EtOAc, 90:10) = 0.20.

(1.8 mL, 20.13 mmol) in a mixture of dry THF (1.5 mL) and dry

2-Me-THF (1.5 mL) was added dropwise. Stirring was continued

at –87 °C for 45 min, and then the reaction mixture was diluted

with a saturated aqueous NH₄Cl solution (15 mL) and Et₂O

(30 mL). Water (30 mL) was added at 0 °C to dissolve the salts.

The layers were separated, and the aqueous layer was extracted

with Et₂O (3ϫ40 mL). The combined organic layers were washed

with brine (100 mL) and dried with anhydrous MgSO₄. After fil-

tration, the solvent was removed in vacuo, and the residue was

purified by chromatography on silica gel (hexane and then hexane/

Et₂O gradually to 50:50) to give compound 12 (0.19 g, 0.84 mmol,

21%) in the second fraction, compound 14 (0.11 g, 0.49 mmol,

11%) in the third fraction and compound 13 (0.23 g, 1.24 mmol,

30%) in the fourth fraction. Two signal sets were observed in the

¹H NMR spectrum (ratio 60:40), which were assigned to the cis

(major) and trans (minor) isomers. The signals of the trans isomer

are hidden by those of the cis isomer in the ¹H NMR spectrum.

IR (KBr film): ν = 3079 (vw), 2974 (s), 2935 (m), 2872 (w), 1735

˜

4652

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4642–4661

Alkylation of Model Compounds of Nonactic Acids

3

They cannot be unambiguously assigned in the ¹³C NMR spec-

1.38–1.26 (m, 1 H, 3aЈ-H), 1.23 (t, J_H8,H7= J_H8Ј,H7Ј= 7.1 Hz, 6

3

trum. R_f(hexane/EtOAc, 90:10) = 0.33. GC (temp. progr. 1): t_R

=

H, 8-H, 8Ј-H), 1.18 (d, J_H9,H4,obs.= J_H9Ј,H4Ј= 6.1 Hz, 6 H, 9-H,

17.89 (isomer 2, cis-12, 62%), 18.09 min (isomer 2, trans-12, 32%).

9Ј-H), 1.08 (s, 6 H, 10-H, 10Ј-H) ppm. ¹³C NMR (100 MHz,

¹H NMR (400 MHz, CDCl₃, 298 K): δ = 5.76–5.65 (m, J_H12,H11aCDCl₃, 298 K): δ = 175.4, 175.5 (C-6, C-6Ј), 134.6 (C-12, C-12Ј),

3

=

³J_{H12Ј,H11aЈ,obs.}= 7.0, J_H12,H13b

=

³J_H12Ј,H13bЈ= 17.0 Hz, 2 H, 118.1 (C-13, C-13Ј), 80.2, 80.3 (C-1, C-1Ј), 76.5, 75.8 (C-4, C-4Ј),

3

12-H, 12Ј-H), 5.07–5.01 (m, J_H13b,H12= J_H13bЈ,H12Ј= 17.0 Hz, 4

H, 13b-H, 13bЈ-H, 13a-H, 13aЈ-H), 4.25–4.06 (m, J_H8,H7

60.7 (C-7, C-7Ј), 50.2 (C-5, C-5Ј), 42.4, 42.1 (C-11, C-11Ј), 33.6,

34.4 (C-3, C-3Ј), 28.1, 27.5 (C-2, C-2Ј), 21.5, 21.2 (C-9, C-9Ј), 16.2,

3

=

³J_H8Ј,H7Ј= 7.1 Hz, 6 H, 7-H, 7Ј-H, 1Ј-H, 4Ј-H), 4.07 (≈t, ³J_H1,H2,obs.16.1 (C-10, C-10Ј), 14.7 (C-8, C-8Ј) ppm. MS (ESI⁺): m/z (%) =

3

≈ 7.3 Hz, 1 H, 1-H), 3.98 (≈dquint, J_H4,H9≈ J_{H4,H3a or H3b}≈ 6.1,

227.32 (100) [M + H]⁺. Method C. From Thione Esters. Procedure

³J_{H4,H3b or H3a,obs.}≈ 7.4 Hz, 1 H, 4-H), 2.53–2.48 (m, J_{H11a,H12,obs.}1: m-CPBA (70%, 130 mg, 0.76 mmol) was added portionwise to a

3

=

7.0 Hz,

1

H, 11a-H), 2.28 (≈dd, J_{H11aЈ,H11bЈ}

=

13.4,

solution of thione ester 21 (21a/21b, 87:13, 140.4 mg, 0.58 mmol)

in dry CH₂Cl₂(9 mL) under argon. The resulting mixture was

³J_{H11aЈ,H12Ј,obs.}= 7.0 Hz, 1 H, 11aЈ-H), 2.16–2.01 (m, J_H11b,H11a

=

3

13.4 Hz, 2 H, 11b-H, 11bЈ-H), 2.00–1.70 (m, 6 H, 3a-H, 3aЈ-H, 2a- stirred at room temperature for 22 h and then treated with a satu-

H, 2aЈ-H, 2b-H, 2bЈ-H), 1.53–1.41 (m, 1 H, 3bЈ-H), 1.39–1.33 (m, rated aqueous NaHCO₃solution (10 mL). Stirring was continued

3

1 H, 3b-H), 1.25 (t, J_H8,H7= 7.1 Hz, 3 H, 8-H), 1.24 (t, J_H8Ј,H7Јfor 15 min, the layers were separated, and the organic layer was

3

= 7.1 Hz, 3 H, 8Ј-H), 1.19 (d, J_H9,H4= 6.1 Hz, 3 H, 9-H), 1.18 (d, washed with brine (10 mL) and dried with anhydrous MgSO₄. Af-

³J_H9Ј,H4Ј= 6.1 Hz, 3 H, 9Ј-H), 1.11 (s, 3 H, 10-H), 1.10 (s, 3 H,

ter filtration, the solvent was removed in vacuo, and the residue was

10Ј-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K): δ = 175.4, 175.3 purified by chromatography on silica gel (hexane and then hexane/

(C-6, C-6Ј), 133.9 (C-12, C-12Ј), 117.9 (C-13, C-13Ј), 83.6, 83.10

(C-1, C-1Ј), 75.9, 75.3 (C-4, C-4Ј), 60.4, 60.2 (C-7, C-7Ј), 50.0, 49.4

EtOAc, 97:3) to give the title compound 12 as a yellow oil (37.7 mg,

0.167 mmol, 29%). Procedure 2: Under argon, a mixture of thione

(C-5, C-5Ј), 40.4, 40.1 (C-11, C-11Ј), 34.0, 32.9 (C-2, C-2Ј), 27.3, ester 21 (21a/21b, 87:13, 200 mg, 0.82 mmol) and bis(tri-n-butyltin)

26.2 (C-3, C-3Ј), 21.2, 21.0 (C-9, C-9Ј), 16.4, 16.2 (C-10, C-10Ј), oxide (566 mg, 0.95 mmol) in dioxane (10 mL) was heated under

14.2 (C-8, C-8Ј) ppm. GC–MS (EI, 70 eV): t_R= 10.22 min (isomer reflux with stirring for 8.5 h. The progress of the reaction was

2, cis-12). GC–MS (EI, 70 eV): m/z (%) = 227.27 (40) [M + H]⁺,

185.33 (20) [M – 41]⁺, 139.24 (65) [M – 87]⁺, 114.24 (20)

monitored by TLC. Further bis(tri-n-butyltin) oxide (0.43 mL,

0.84 mmol) and dioxane (2 mL) were added, and the resulting mix-

[M – 112]⁺, 85.31 (50) [M – 141]⁺, 67.23 (100) [M – 159]⁺. GC–MS ture was heated at reflux for 16 h. Additional bis(tri-n-butyltin) ox-

(EI, 70 eV): t_R= 10.39 min (isomer 2, trans-12). GC–MS (EI, ide (0.43 mL, 0.84 mmol) and dioxane (2 mL) were then added, and

70 eV): m/z (%) = 227.27 (17) [M + H]⁺, 185.24 (13) [M – 41]⁺,

139.23 (42) [M – 87]⁺, 114.23 (20) [M – 112]⁺, 85.24 (46) [M –

141]⁺, 67.22 (100) [M – 159]⁺. HRMS: calcd. for [C₁₃H₂₂O₃Na]⁺

the mixture was heated under reflux for 24 h until total conversion.

The crude product was purified by chromatography on silica gel

(hexane and then hexane/EtOAc, 95:5) to give the title compound

249.14611; found 249.14602. HRMS: calcd. for C₁₃H₂₂O₃12 as a yellow oil and as a mixture of two isomers in 66% overall

[M + H]⁺227.16417; found 227.16417. Method B: Allyltributyltin

(0.39 mL, 1.28 mmol) was added dropwise to a solution of iodo

yield (cis/trans, 90:10, 132 mg, 0.58 mmol). Traces of bis(tri-n-

butyltin) were observed by NMR spectroscopy. Procedure 3: Under

ester 15 (200 mg, 0.64 mmol) in dry hexane (6.5 mL) under argon argon, a mixture of thione ester 21 (21a/21b, 87:13, 288 mg,

at 25 °C. After disappearance of a rose colour, AIBN (21 mg,

0.13 mmol) was added, and the reaction mixture was stirred at re-

flux for 12 h. The resulting mixture was cooled to 25 °C, and a

diluted saturated aqueous NaCl solution (30 mL) and Et₂O

(30 mL) were added. The layers were separated, the aqueous layer

was extracted with Et₂O (30 mL), and the combined organic layers

were dried with anhydrous MgSO₄. After filtration, the solvent was

removed in vacuo, and the residue was purified by chromatography

on silica gel (hexane/EtOAc, 90:10) to give the title compound 12

as a mixture of two isomers in a ratio of 55:45 in 66% overall yield

1.19 mmol) and di-n-butyltin oxide (470 mg, 1.9 mmol) in dioxane

(6 mL) was heated under reflux with stirring for 29 h. The progress

of the reaction was monitored by TLC. Then further di-n-butyltin

oxide (200 mg, 0.80 mmol) and dioxane (2 mL) were added, and

the resulting mixture was heated at reflux for another 27 h. The

conversion being about 60% (¹H NMR), the reaction mixture was

heated at reflux for a further 92 h (77% conversion). The mixture

was filtered through a mixture of Celite/silica gel (30:70) and

washed with dioxane. The solvent was removed in vacuo and the

residue taken up in dioxane (6 mL) under argon. Di-n-butyltin ox-

(95 mg, 0.42 mmol). Traces of allyltributyltin were observed. R_fide (300 mg, 1.2 mmol) was then added, and the resulting mixture

(hexane/EtOAc, 90:10) = 0.25. GC (temp. progr. 1): t_R= 17.44

(isomer 1, cis-12a, 43%), 17.73 min (isomer 1, trans-12c, 57%). IR

was heated under reflux for 48 h until total conversion. The crude

product was purified by chromatography on silica gel (from hexane

(KBr film): ν = 3077 (w), 2975 (vs), 2932 (s), 2873 (m), 2110 (vw), gradually to hexane/EtOAc, 90:10) to give the title compound 12

˜

1730 (vs), 1641 (w), 1464 (m), 1445 (m), 1383 (m), 1287 (m), 1217 as a yellow oil (130 mg, 57 mmol, 48%). R_f(hexane/EtOAc, 90:10)

(s), 1144 (s), 1093 (s), 1024 (s), 916 (w), 859 (vw), 668 (vw) cm^–1. = 0.40 (isomer 1, cis-12a), 0.30 (isomer 1, trans-12c). GC (temp.

3

¹H NMR (400 MHz, CDCl₃, 298 K): δ = 5.80–5.70 (m, J_H12,H13aprogr. 2): t_R= 7.00 min (isomer 1, cis-12a, 90%), 7.07 min (isomer

3

= J_H12Ј,H13aЈ= 10.1, J_H12,H13b= J_H12Ј,H13bЈ= 17.0 Hz, 2 H, 11- 1, trans-12c, 10%). IR (KBr film): ν = 3078 (vw), 2975 (vs), 2931

˜

3

H, 11Ј-H), 5.02 (m, J_H13b,H12= J_H13bЈ,H12Ј= 17.0 Hz, 2 H, 13b-

(s), 2873 (m), 1732 (vs), 1641 (w), 1464 (m), 1379 (m), 1291 (m),

3

H, 13bЈ-H), 5.00 (m, J_H13a,H12= J_H13aЈ,H12Ј= 10.0 Hz, 2 H, 13a- 1218 (s), 1143 (s), 1093 (vs), 1058 (m), 1022 (s), 916 (m), 859 (vw),

H, 13aЈ-H), 4.13 (≈t, J_H1Ј,H2Ј≈ 6.9 Hz, 1 H, 1Ј-H), 4.11 (≈q, 662 (vw) cm^–1. cis-12a: ¹H NMR (400 MHz, CDCl₃, 298 K): δ =

3

³J_H7,H8= J_H7Ј,H8Ј= 7.1 Hz, 4 H, 7-H, 7Ј-H), 4.05–3.99 (m, 1 H, 5.71 (dddd, J_H12,H13b= 17.0, J_H12,H13a= 10.1, J_H12,H11b= 8.0,

4-H), 4.03 (≈t, J_H1,H2≈ 7.2 Hz, 1 H, 1-H), 3.92 (≈dquint, ³J_H12,H11a= 6.8 Hz, 1 H, 12-H), 5.04 (ddt, J_H13b,H12= 17.0,

3

³J_{H4Ј,H3aЈ or 3bЈ-H}≈ 8.0, J_H4Ј,H9Ј

≈

³J_{H4Ј,H3bЈ or 3aЈ-H}≈ 6.1 Hz, 1 H, ²J_H13b,H13a= 2.3, ⁴J_{H13b,H11b and H11a,obs.}≈ 1.3 Hz, 1 H, 13b-H), 5.02

3

2

4

4Ј-H), 2.51 (dd, J_H11b,H12= J_H11bЈ,H12Ј= 13.6, J_{H11b,H13a or H13b}(ddt, J_H13a,H12= 10.1, J_H13a,H13b= 2.3, J_{H13a,H11b and H11a}

=

2

3

=

³J_{H11bЈ,H13aЈ or 13bЈ-H}= 6.8 Hz, 2 H, 11b-H, 11bЈ-H), 2.29 (dt,

1.0 Hz, 1 H, 13a-H), 4.13 (dq, J_H7a,H7b= 10.8, J_H7a,H8= 7.1 Hz,

3

2

3

³J_H11a,H12= J_H11aЈ,H12Ј= 13.6, J_H11b,H13= J_H11bЈ,H13Ј= 8.3 Hz, 1 H, 7a-H), 4.10 (dq, J_H7b,H7a= 10.8, J_H7b,H8= 7.1 Hz, 1 H, 7b-

3

2 H, 11a-H, 11aЈ-H), 2.00–1.71 (m, 5 H, 3b-H, 3bЈ-H, 2b-H, 2bЈ- H), 4.04 (≈dd, J_H1,H2a= 7.1, J_H1,H2b= 7.5 Hz, 1 H, 1-H), 3.94

H, 2a-H), 1.69–1.59 (m, 1 H, 2aЈ-H), 1.49–1.39 (m, 1 H, 3a-H), (dquint, J_H4,H3a= 7.8, J_H4,H9

3

=

³J_H4,H3b= 6.0 Hz, 1 H, 4-H),

Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

4653

F. Loiseau, I. Kholod, R. Neier

FULL PAPER

2

3

2.52 (m, J_H11a,H11b= 13.6, J_H11a,H12= 6.8 Hz, 1 H, 11a-H), 2.28

(w), 863 (vw) cm^–1. ¹H NMR (400 MHz, CDCl₃, 298 K): δ = 5.72–

2

3

4

3

(≈ddt, J_H11b,H11a= 13.6, J_H11b,H12= 8.0, J_{H11b,H13a and H13b}

=

5.68 (m, 2 H, 12-H, 12Ј-H), 5.69 (≈dt, J_H3,H4= J_H3Ј,H4Ј= 15.8,

3

1.0 Hz, 1 H, 11b-H), 1.92 (dddd, J_H3b,H3a= 11.6, J_H3b,H2b= 8.4, ³J_H3,H5= J_H3Ј,H5Ј= 1.2 Hz, 2 H, 3-H, 3Ј-H), 5.52–5.45 (m, 1 H,

2

3

³J_H3b,H4= 6.0, ³J_H3b,H2a= 5.0 Hz, 1 H, 3b-H), 1.83 (≈ddt, ²J_H2b,H2a4Ј-H), 5.49 (dt, J_H4,H3= 15.8 Hz, 1 H, 4-H), 5.06–5.02 (m, 4 H,

3

= 12.3, J_H2b,H3b= 8.4, J_H2b,H1≈ J_H2b,H3a≈ 7.8 Hz, 1 H, 2b-H),

13-H, 13Ј-H), 4.12 (q, J_H8,H9= J_H8Ј,H9Ј= 7.1 Hz, 4 H, 8-H, 8Ј-

1.72 (dddd, J_H2a,H2b= 12.3, J_H2a,H3a= 9.3, J_H2a,H1= 7.1 Hz, H), 3.79 (≈dquint, ³J_{H6Ј,H5Ј,obs.}= 7.5, ³J_H6Ј,H7Ј= ³J_H6Ј,H5Ј= 6.2 Hz,

2

3

2

3

³J_H2a,H3b= 5.0 Hz, 1 H, 2a-H), 1.33 (≈ddt, J_H3a,H3b= 11.6,

1 H, 6Ј-H), 3.79 (≈dquint, J_H6,H5,obs.= 7.5, J_H6,H7

=

³J_H6,H5

=

³J_H3a,H2a= 9.3 Hz, J_H3a,H4≈ J_H3a,H2b≈ 7.8 Hz, 1 H, 3a-H), 1.23 6.1 Hz, 1 H, 6-H), 2.45 (br. dt, J_{H11b,H11a,obs.}= J_{H11bЈ,H11aЈ,obs.}

3

2

3

(t, J_H8,H7= 7.1 Hz, 3 H, 8-H), 1.20 (d, J_H9,H4= 6.0 Hz, 3 H, 9-

14.3, J_{H11b,H12,obs.}= J_{H11bЈ,H12Ј,obs.}= 7.0 Hz, 2 H, 11b-H, 11bЈ-

H), 1.09 (s, 3 H, 10-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K):

H), 2.34 (≈ddt, J_{H11a,H11b,obs.}

³J_{H11aЈ,H12Ј,obs.}

=

²J_{H11aЈ,H11bЈ,obs.}

7.2, ⁴J_{H11a,H13,obs.}

= 13.7,

2

δ = 175.1 (C-6), 134.2 (C-12), 117.7 (C-13), 82.9 (C-1), 75.4 (C-4), ³J_{H11a,H12,obs.}

=

60.3 (C-7), 49.8 (C-5), 41.7 (C-11), 33.2 (C-3), 27.1 (C-2), 20.7 (C- ⁴J_{H11aЈ,H13Ј,obs.}= 1.2 Hz, 2 H, 11a-H, 11aЈ-H), 2.27–2.20 (m,

9), 15.8 (C-10), 14.3 (C-8) ppm. MS (APCI⁺): m/z (%) = 228.0 (16)

²J_H5b,H5a

=

²J_H5bЈ,H5aЈ= 13.6 Hz, 2 H, 5b-H, 5bЈ-H), 2.13 (dtd,

[M + 2 H]⁺, 226.90 (100) [M + H]⁺, 181.00 (9) [M – OEt]⁺, 153.10 ²J_H5a,H5b

²J_H5aЈ,H5bЈ= 13.6, J_H5a,H6

= = =

³J_H5aЈ,H6Ј³J_H5a,H4

3

4

(10).

³J_H5aЈ,H4Ј= 7.5, J_H5a,H3= J_H5aЈ,H3Ј= 1.0 Hz, 2 H, 5a-H, 5aЈ-H),

3

1.89 (br., 2 H, OH), 1.26 (s, 6 H, 10-H, 10Ј-H), 1.23 (t, J_H9,H8

=

³J_H9Ј,H8Ј= 7.1 Hz, 6 H, 9-H, 9Ј-H), 1.17 (d, J_H7,H6= 6.2 Hz, 3

3

H, 7-H), 1.16 (d, J_H7Ј,H6Ј= 6.20 Hz, 3 H, 7Ј-H) ppm. ¹³C NMR

3

(100 MHz, CDCl₃, 298 K): δ = 175.5 (C-1, C-1Ј), 136.9 (C-3, C-

3Ј), 133.9, 133.8 (C-12, C-12Ј), 125.6, 125.5 (C-4, C-4Ј), 118.2 (C-

13, C-13Ј), 69.9, 66.9 (C-6, C-6Ј), 60.7 (C-8, C-8Ј), 47.7 (C-2, C-

2Ј), 43.5, 43.4 (C-11, C-11Ј), 42.4 (C-5, C-5Ј), 22.5 (C-7, C-7Ј), 21.1,

21.0 (C-10, C-10Ј), 14.1 (C-9, C-9Ј) ppm. MS (APCI⁺): m/z (%) =

228.0 (14) [M + 2]⁺, 226.9 (100) [M + H]⁺, 275.0 (32) [M – 1]⁺,

210.1 (12) [M – 16]⁺, 209.1 (86) [M – 17]⁺, 156.9 (12) [M – 69]⁺.

HRMS: calcd. for [C₁₃H₂₂O₃Na]⁺249.1461; found 249.14611.

Ethyl (E)-6-Hydroxy-2-methylhept-2-enoate (13): LiHMDS

(2.6 mmol, 2.6 mL) was added to dry THF (2 mL) at –55 °C under

argon. A solution of ester 7 (250 mg, 1.34 mmol) in dry THF

(2 mL) was then added dropwise over 10 min. Stirring was contin-

ued at –55 °C for 4 h, and then the reaction mixture was diluted

portionwise with a 2  aqueous HCl solution (3.35 mL) and then

with Et₂O (20 mL). The mixture was allowed to reach room tem-

perature. The layers were separated, and the aqueous layer was ex-

tracted with Et₂O (3ϫ15 mL). The combined organic layers were

washed with brine (25 mL) and dried with anhydrous MgSO₄. Af-

ter filtration, the solvents were evaporated, and the residue was

purified by chromatography on silica gel (hexane/EtOAc gradually

from 90:10 and to 75:25) to give the alcohol 13 as a colourless oil

(0.96 mg, 5.15 mmol, 39%). R_f(hexane/EtOAc, 75:25) = 0.21. GC

Ethyl 2-Iodo-2-(5-methyltetrahydrofuran-2-yl)propanoate (15): NIS

(0.62 g, 2.78 mmol) was added to a solution of acrylate 13 (0.41 g,

2.22 mmol) in dry CH₂Cl₂(12 mL) under argon. The reaction mix-

ture was stirred at room temperature for 4 h, and then more NIS

(0.25 g, 1.11 mmol) was added. The resulting mixture was stirred

in the dark at 30 °C for 16 h, and then the reaction mixture was

diluted with a saturated aqueous Na₂S₂O₃solution (20 mL) and

CH₂Cl₂(10 mL). The layers were separated, and the aqueous layer

was extracted with CH₂Cl₂(2ϫ20 mL). The combined organic lay-

ers were washed with brine (50 mL) and dried with anhydrous

MgSO₄. After filtration, the solvent was removed in vacuo, and the

residue was purified by chromatography on silica gel (hexane and

then hexane/EtOAc, 90:10) to give the title compound 15 as a mix-

ture of two isomers in a ratio of 55:45 and in 74% overall yield

(0.51 g, 1.63 mmol). R_f(hexane/EtOAc, 90:10) = 0.42. IR (KBr

(temp. progr. 1): t_R= 18.40 min (100%). IR (KBr film): ν = 3436

˜

(br), 2969 (m), 2930 (m), 1710 (vs), 1648 (w), 1448 (w), 1369 (m),

1271 (vs), 1193 (m), 1138 (s), 1096 (m), 1030 (w), 974 (vw), 936

(vw), 869 (vw), 746 (vw) cm^–1. ¹H NMR (400 MHz, CDCl₃,

3

4

298 K): δ = 6.75 (tq, J_H3,H4,obs.= 7.5, J_H3,H10≈ 1.2 Hz, 1 H, 3-

3

H), 4.17 (q, J_H8,H9= 7.1 Hz, 2 H, 8-H), 3.81 (≈sext, J_H6,H7

≈

³J_H6,H5≈ 6.1 Hz, 1 H, 6-H), 2.32–2.21 (m, J_H4,H3= 7.5 Hz, 2 H,

4-H), 1.83 (≈d, ⁴J_H10,H3≈ 1.2 Hz, 3 H, 10-H), 1.62–1.57 (m, ³J_H5,H6

= 6.1 Hz, 3 H, 5-H, OH), 1.28 (t, ³J_H9,H8= 7.1 Hz, 3 H, 9-H), 1.20

(d, ³J_H7,H6= 6.1 Hz, 3 H, 7-H) ppm. ¹³C NMR (100 MHz, CDCl₃,

298 K): δ = 167.6 (C-1), 142.0 (C-3), 128.5 (C-2), 67.8 (C-6), 60.0

(C-8), 38.2 (C-5), 25.4 (C-4), 24.0 (C-7), 14.7 (C-9), 12.7 (C-10)

ppm. MS (EI, 70 eV): m/z (%) = 188.22 (11) [M + 2 H]⁺, 187.19

(100) [M + H]⁺, 141.34 (15) [M – OEt]⁺, 95.38 (21). HRMS: calcd.

for [C₁₀H₁₈O₃Na]⁺209.11481; found 209.11447.

3

film): ν = 2975 (m), 2931 (w), 2871 (w), 2110 (vw), 1730 (vs), 1446

˜

(m), 1377 (w), 1330 (vw), 1297 (w), 1252 (s), 1196 (w), 1128 (m),

1085 (s), 1049 (m), 1024 (m), 970 (vw), 898 (vw), 873 (vw), 862

(vw), 588 (vw) cm^–1. ¹H NMR (400 MHz, CDCl₃, 298 K): δ = 4.49

(dd, ³J_H1,H2a= 7.1, ³J_H1,H2b= 8.0 Hz, 1 H, 1-H), 4.37 (dd, ³J_H1Ј,H2aЈ

3

= 5.8, J_H1Ј,H2bЈ= 8.0 Hz, 1 H, 1Ј-H), 4.28–4.15 (m, J_H4,H9

=

3

6.1 Hz, 1 H, 4-H), 4.24 (q, J_H7,H8= 7.1 Hz, 2 H, 7-H), 4.23 (q,

³J_H7Ј,H8Ј= 7.1 Hz, 2 H, 7Ј-H), 4.11–4.06 (m, J_H4Ј,H9Ј= 6.0 Hz, 1

3

Ethyl (E)-2-Allyl-6-hydroxy-2-methylhept-3-enoate (14): The acry-

late 14 was obtained as a mixture of two isomers in a ratio of 65:35

H, 4Ј-H), 2.36–2.29 (m, J_H2a,H1= 7.1 Hz, 1 H, 2a-H), 2.24–2.19

3

(m, J_H2aЈ,H1Ј= 5.8 Hz, 1 H, 2aЈ-H), 2.10–1.92 (m, J_H2b,H1

=

in 11% overall yield (0.11 g, 0.49 mmol) according to the procedure ³J_H2bЈ,H1Ј= 8.0 Hz, 4 H, 2b-H, 2bЈ-H, 3aЈ-H, 3a-H), 2.03 (s, 1 H,

given for compound 12 (Method A). R_f(hexane/EtOAc, 75:25) =

10-H), 2.01 (s, 1 H, 10Ј-H), 1.60–1.42 (m, 2 H, 3b-H, 3bЈ-H), 1.29

3

0.33. IR (KBr film): ν = 3427 (br), 3079 (vw), 2978 (s), 2933 (m),

(t, ³J_H8,H7= 7.1 Hz, 3 H, 8-H), 1.28 (t, J_H8Ј,H7Ј= 7.1 Hz, 3 H, 8Ј-

˜

3

1729 (vs), 1641 (w), 1457 (m), 1378 (m), 1285 (m), 1230 (s), 1180 H), 1.20 (d, J_H9Ј,H4Ј= 6.0 Hz, 3 H, 9Ј-H), 1.18 (d, J_H9,H4

(m), 1143 (s), 1118 (s), 1077 (m), 1023 (m), 995 (w), 976 (m), 918

=

6.1 Hz, 3 H, 9-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K): δ =

4654

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4642–4661

Alkylation of Model Compounds of Nonactic Acids

3

172.1, 172.0 (C-6, C-6Ј), 83.4, 83.0 (C-1Ј, C-1), 77.8, 77.7 (C-4, C-

3 H, 8-H), 1.34 (d, J_H10,H5= 6.8 Hz, 3 H, 10-H), 1.22 (d,

4Ј), 61.9 (C-7, C-7Ј), 44.8, 44.1 (C-5,C-5Ј), 34.5, 33.1 (C-3, C-3Ј), ³J_H9,H4,obs.= 6.1 Hz, 3 H, 9-H) ppm. ¹³C NMR (100 MHz, CDCl₃,

31.0, 30.4 (C-2, C-2Ј), 24.5, 24.2 (C-10, C-10Ј), 21.2, 20.7 (C-9, C-

9Ј), 13.6 (C-8, C-8Ј) ppm.

298 K): δ = 225.8 (C-6), 82.3 (C-1), 75.6 (C-4), 67.8 (C-7), 56.7 (C-

5), 32.7 (C-3), 29.5 (C-2), 21.4 (C-9), 18.0 (C-10), 13.5 (C-8) ppm.

MS (EI, 70 eV): m/z (%) = 203.11 (7) [M + H]⁺, 173.14 (4) [M –

Et]⁺, 169.14 (19), 156.02 (51) [M – EtOH]⁺, 141.08 (14), 117.06

(30), 99.09 (98), 98.09 (82), 85.12 (66), 83.12 (14), 67.11 (100), 57.15

(69). cis-18a: 80 mg, 0.40 mmol, 15%. ¹H NMR (400 MHz, CDCl₃,

2

3

298 K): δ = 4.55 (dq, J_H7a,H7b= 11.0, J_H7a,H8= 7.1 Hz, 1 H, 7a-

2

3

H), 4.51 (dq, J_H7b,H7a= 11.0, J_H7b,H8= 7.1 Hz, 1 H, 7b-H), 4.11

(≈dt, ³J_H1,H5= 8.0, ³J_H1,H2a/H2b= 6.8 Hz, 1 H, 1-H), 3.98 (≈dquint,

³J_{H4,H3a or H3b,obs.}= 7.3, ³J_{H4,H3b or H3a,obs.}= ³J_H4,H9= 6.1 Hz, 1 H,

Thionation of Esters

3

O-Ethyl 2-(5-Methyltetrahydrofuran-2-yl)thioacetate (17): Under

argon, P₄S₁₀(3.92 g, 8.8 mmol) and HMDO (19 mL, 88.2 mmol)

were dissolved in dry toluene at 100 °C. The reaction mixture was

stirred for 10 min and then heated at reflux. Ester 5 (5.0 g,

29 mmol) was added dropwise, and the resulting mixture was

heated at reflux for 16 h. After being cooled to 0 °C, the reaction

mixture was treated with an aqueous 5% NaHCO₃solution

(20 mL), and the layers were separated. The aqueous layer was ex-

tracted with Et₂O (200 mL), and the combined organic layers were

dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo.

Toluene was removed by vacuum distillation at 20 Torr, and the

residue was purified by chromatography on silica gel (hexane and

then hexane/Et₂O, 90:10) to give the thione ester 17 as a mixture

of two isomers in a ratio of 85:15 and in 42% overall yield (2.3 g,

4-H), 2.93 (dq, J_H5,H1= 8.0, J_H5,H10= 6.9 Hz, 1 H, 5-H), 2.03–

3

1.89 (m, 2 H, 3a-H, 2a-H), 1.73–1.64 (m, J_H2a,H1= 6.8 Hz, 1 H,

2b-H), 1.47–1.38 (m, 1 H, 3b-H), 1.39 (t, J_H8,H7= 7.1 Hz, 3 H, 8-

3

H), 1.19 (d, ³J_H9,H4= 6.1 Hz, 3 H, 9-H), 1.16 (d, ³J_H10,H5= 6.9 Hz,

3 H, 10-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K): δ = 226.5

(C-6), 82.5 (C-1), 75.5 (C-4), 67.9 (C-7), 55.9 (C-5), 32.6 (C-3), 28.7

(C-2), 21.4 (C-9), 16.6 (C-10), 13.5 (C-8) ppm. MS (EI, 70 eV): m/z

(%) = 204.15 (8) [M + 2 H]⁺, 203.06 (69) [M + H]⁺, 202.03 (13)

[M]⁺, 173.14 (6) [M – Et]⁺, 169.12 (28), 156.02 (76) [M – EtOH]⁺,

141.13 (16), 117.06 (27), 99.09 (100), 98.09 (60), 85.13 (89), 83.10

(16), 67.12 (94), 57.09 (69). HRMS: calcd. for [C₁₀H₁₈O₂SNa]⁺

225.09252; found 225.09254.

1

12.16 mmol). Two signal sets were observed in the H NMR spec-

trum, which were assigned to the cis (major) and trans (minor)

isomers. R (hexane/EtOAc, 95:5) = 0.31. IR (KBr film): ν = 2970

˜

f

(vs), 2871 (s), 2873 (m), 1445 (m), 1372 (m), 1372 (s), 1300 (vs),

1260 (vs), 1201 (vs), 1170 (s), 1091 (vs), 1020 (s), 923 (w), 911 (w),

879 (vw), 810 (vw) cm^–1. cis-17: ¹H NMR (400 MHz, CDCl₃,

Alkylation of Thione Esters

3

298 K): δ = 4.51 (q, J_H7,H8= 7.1 Hz, 2 H, 7-H), 4.37 (quint,

³J_H1,H2,obs.

=

³J_H1,H5,obs.= 6.6 Hz, 1 H, 1-H), 4.00 (dquint,

O-Ethyl

2-(5-Methyltetrahydrofuran-2-yl)-2-(3-oxocyclopentyl)-

3

³J_H4,H3b,obs.= 7.6, J_H4,H9= J_H4,H3a,obs.= 6.1 Hz, 1 H, 4-H), 3.07

thioacetate (19): nBuLi (1.6  in hexane, 0.8 mL, 1.29 mmol) was

added dropwise to a solution of diisopropylamine (0.21 mL,

1.49 mmol) in dry THF (3 mL) under argon at 0 °C. The mixture

was stirred for 30 min and then cooled to –78 °C, and a solution

of thione ester 17 (200 mg, 1.06 mmol, 2,5-cis/2,5-trans, 90:10) in

dry THF (3 mL) was added dropwise. Stirring was continued at

–78 °C for 20 min, and then a solution of cyclopentenone (0.13 mL,

1.59 mmol) in dry THF (1 mL) was added dropwise. The reaction

mixture was allowed to reach –40 °C, stirred at this temperature

for 1 h and then treated with saturated aqueous NH₄Cl solution

(10 mL) and Et₂O (50 mL). The layers were separated, and the

aqueous layer was extracted with Et₂O (2ϫ10 mL). The combined

organic layers were washed with brine (10 mL) and dried with an-

hydrous MgSO₄. After filtration, the solvent was removed in vacuo,

and the residue was purified by chromatography on silica gel (hex-

ane/Et₂O, 90:10) to give the title compound 19 as a yellow oil and

as a mixture of two enantiomers in a ratio of 75:25 and in 52%

overall yield (150 mg, 55 mmol). R_f(hexane/EtOAc, 75:25) = 0.27.

2

3

(dd, J_H5a,H5b= 14.1, J_H5a,H1= 6.5 Hz, 1 H, 5a-H), 2.85 (dd,

²J_H5b,H5a= 14.1, ³J_H5b,H1= 6.8 Hz, 1 H, 5b-H), 2.10–1.95 (m, 2 H,

3b-H, 2a-H), 1.73–1.65 (m, 1 H, 2b-H), 1.54–1.45 (m, 1 H, 3a-H),

3

1.41 (t, J_H8,H7= 7.1 Hz, 3 H, 8-H), 1.24 (d, J_H9,H4= 6.1 Hz, 3

H, 9-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K): δ = 220.7 (C-

6), 76.1 (C-1), 75.3 (C-4), 68.6 (C-7), 54.0 (C-5), 33.0 (C-3), 31.3

(C-2), 21.9 (C-9), 14.0 (C-8) ppm. MS (APCI⁺): m/z (%) = 188.9

(100) [M + H]⁺. HRMS: calcd. for [C₉H₁₆O₂SNa]⁺211.07687;

found 211.07637.

O-Ethyl 2-(5-Methyltetrahydrofuran-2-yl)propanethioate (18): Ac-

cording to the procedure reported for compound 17 (Method B),

HMDO (1.7 mL, 8.1 mmol), P₄S₁₀(0.36 g, 0.81 mmol), and ester 7 IR (KBr film): ν = 2969 (s), 2934 (w), 2873 (w), 1744 (vs), 1459

˜

(0.5 g, 2.7 mmol) reacted to give two isomers of 18 in 30% overall

yield after chromatography on silica gel (hexane/Et₂O, 90:10). R_f

(hexane/EtOAc, 90:10) = 0.30 (cis isomer 1, 18b), 0.25 (cis isomer

2, 18a). Four pairs of enantiomers were observed. GC (temp. progr.

2): t_R= 6.41 (isomer 1, cis-18b, 36%), 6.48 (isomer 1, trans-18c,

4%), 6.58 (isomer 2, cis-18a, 58%), 6.85 (isomer 2, trans-18d, 2%).

cis-18b: 80 mg, 0.40 mmol, 15%. ¹H NMR (400 MHz, CDCl₃,

(vw), 1402 (vw), 1372 (w), 1314 (m), 1292 (m), 1228 (m), 1192 (m),

1

1162 (s), 1088 (m), 1017 (w), 894 (vw) cm^–1. H NMR (400 MHz,

CDCl₃, 298 K): δ = 4.50 (dq, ²J_H7aЈ,H7bЈ= 12.1, ³J_H7aЈ,H8Ј= 7.1 Hz,

2

3

1 H, 7aЈ-H), 4.48 (dq, J_H7bЈ,H7aЈ= 12.1, J_H7bЈ,H8Ј= 7.1 Hz, 1 H,

2

3

7bЈ-H), 4.47 (dq, J_H7a,H7b= 12.1, J_H7a,H8= 7.1 Hz, 1 H, 7a-H),

4.47 (dq, ²J_H7b,H7a= 12.1, ³J_H7b,H8= 7.1 Hz, 1 H, 7b-H), 4.29 (ddd,

³J_H1Ј,H5Ј= 9.2, ³J_H1Ј,H2aЈ= 7.4, ³J_H1Ј,H2bЈ= 6.3 Hz, 1 H, 1Ј-H), 4.13

(≈dt, J_H1,H5= 9.0, J_H1,H2≈ 7.8 Hz, 1 H, 1-H), 4.08–3.93 (m,

3

298 K): δ = 4.51 (q, J_H7,H8= 7.1 Hz, 2 H, 7-H), 4.00–3.95 (m,

3

³J_H1,H5= 8.6 Hz, 2 H, H¹, 4-H), 2.90 (dq, J_H5,H1= 8.6, J_H5,H10³J_H9,H4= J_H9Ј,H4Ј= 6.1 Hz, 2 H, 4-H, 4Ј-H), 2.79–2.58 (m, 2 H,

= 6.8 Hz, 1 H, 5-H), 1.99–1.88 (m, 2 H, 3a-H, 2a-H), 1.72–1.65 10-H, 10Ј-H), 2.38–2.23 (m, 6 H, 14a-H, 13a-H, 11a-H, 14aЈ-H,

(m, 1 H, 2b-H), 1.47–1.40 (m, 1 H, 3b-H), 1.39 (t, ³J_H8,H7= 7.1 Hz, 13aЈ-H, 11aЈ-H), 2.22–2.18 (m, 4 H, 13b-H, 11b-H, 13bЈ-H, 11bЈ-

Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

4655

F. Loiseau, I. Kholod, R. Neier

FULL PAPER

H), 2.02–1.88 (m, 4 H, 2a-H, 3a-H, 2aЈ-H, 3aЈ-H), 1.78–1.67 (m, 4

3Ј), 33.4, 32.6 (C-2, C-2Ј), 30.2, 29.4 (C-10, C-10Ј), 21.5, 21.1 (C-

H, 2b-H, 14b-H, 2bЈ-H, 14bЈ-H), 1.48–1.38 (m, 2 H, 3b-H, 3bЈ-H), 9, C-9Ј), 13.6 (C-8, C-8Ј) ppm. MS (APCI⁺): m/z (%) = 229.9 (14)

3

1.37 (t, J_H8,H7= 7.1 Hz, 3 H, 8-H), 1.37 (t, J_H8Ј,H7Ј= 7.1 Hz, 3 [M + H]⁺, 228.9 (100) [M]⁺. HRMS: calcd. for [C₁₂H₂₀O₂SNa]⁺

3

H, 8Ј-H), 1.19 (d, J_H9,H4= 6.1 Hz, 3 H, 9-H), 1.17 (d, J_H9Ј,H4Ј

=

251.10817; found 251.10731. Two pairs of minor enantiomers

6.1 Hz, 3 H, 9Ј-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K): δ = (65:35 ratio, 3%): R_f(hexane/EtOAc, 90:10) = 0.35. ¹H NMR

3

221.9, 218.6 (C-12, C-6), 222.1, 218.6 (C-12Ј, C-6Ј), 80.6 (C-1), 80.3

(C-1Ј), 75.8 (C-4), 75.1 (C-4Ј), 67.8 (C-7), 66.7 (C-7Ј), 65.8 (C-5),

65.4 (C-5Ј), 44.5 (C11Ј), 42.4 (C-11), 40.2 (C10Ј), 40.1 (C-10), 38.8 11Ј-H), 5.02 (dm, J_H12b,H11= J_H12bЈ,H11Ј= 17.0 Hz, 2 H, 12b-H,

(C-13), 38.0 (C-13Ј), 33.2 (C-3Ј), 32.3 (C-3), 29.7 (C-2), 28.3 (C-

2Ј), 28.2 (C-14), 27.2 (C-14Ј), 21.4 (C-9), 21.1 (C-9Ј), 13.5 (C-8, C- 12aЈ-H), 4.62–4.49 (m, J_H7Ј,H8Ј= 7.1 Hz, 2 H, 7Ј-H), 4.58 (dq,

(400 MHz, CDCl₃, 298 K):

δ

=

5.76–5.65 (m, J_H11,H12b

=

³J_H11Ј,H12bЈ= 17.0, J_H11,H12a= J_H11Ј,H12aЈ= 10.1 Hz, 2 H, 11-H,

3

12bЈ-H), 4.95 (dm, ³J_H12a,H11= ³J_H12aЈ,H11Ј= 10.1 Hz, 2 H, 12a-H,

3

2

8Ј) ppm.

²J_H7a,H7b= 11.0, J_H7a,H8= 7.1 Hz, 1 H, 7a-H), 4.53 (dq, J_H7b,H7a

3

= 11.0, J_H7b,H8= 7.1 Hz, 1 H, 7b-H), 4.25 (≈td, J_H1Ј,H5Ј

=

³J_{H1Ј,H2aЈ or H2bЈ,obs.}≈ 8.1, ³J_{H1Ј,H2bЈ or H2aЈ,obs.}= 6.5 Hz, 1 H, 1Ј-H),

3

4.13–4.05 (m, 2 H, 1-H, 4Ј-H), 3.97 (≈dquint, J_{H4,H3a or H3b,obs.}

=

3

7.3, J_{H4,H3b or H3a,obs.}= J_H4,H9= 6.1 Hz, 1 H, 4-H), 3.00 (≈ddd,

³J_{H5Ј,H10aЈ or H10bЈ,obs.}= 10.3, J_H5Ј,H1Ј= 8.1, J_{H5Ј,H10bЈ or H10aЈ,obs.}

3

= 4.0 Hz, 1 H, 5Ј-H), 2.95 (ddd, J_{H5,H10a or H10b,obs.}= 10.6,

³J_H5,H1,obs.= 8.1, J_{H5,H10b or H10a,obs.}= 4.0 Hz, 1 H, 5-H), 2.55–

3

2.40 (m, 2 H, 3a-H, 3aЈ-H), 2.36–2.22 (m, 2 H, 3b-H, 3bЈ-H), 2.10–

2.01 (m, 2 H, 2aЈ-H, 10aЈ-H), 2.00–1.90 (m, 2 H, 2a-H, 10a-H),

1.80–1.64 (m, 2 H, 10b-H, 10bЈ-H), 1.50–1.42 (m, 2 H, 2b-H, 2bЈ-

O-Ethyl 2-(5-Methyltetrahydrofuran-2-yl)pent-4-enethioate (20): A

solution of tBuOK (155 mg, 1.38 mmol) in dry THF (2 mL) was

added dropwise to a solution of thione ester 17 (0.2 g, 1.06 mmol)

in dry THF (4 mL) under argon at –78 °C. The reaction mixture

was stirred at –78 °C for 15 min and then warmed and stirred at

–10 °C for 6 min. Stirring was continued at –78 °C for 10 min, and

then allyl iodide (0.13 mL, 1.38 mmol) was added dropwise. The

resulting mixture was allowed to reach –10 °C and then treated

with a saturated aqueous NH₄Cl solution (10 mL) and Et₂O

(15 mL). The layers were separated, and the aqueous layer was ex-

tracted with Et₂O (2ϫ15 mL). The combined organic layers were

washed with brine (15 mL) and dried with anhydrous MgSO₄. Af-

ter filtration, the solvent was removed in vacuo, and the residue

was purified by chromatography on silica gel (hexane/Et₂O grad-

ually) to give the title compound 20 as a yellow oil in two fractions

in 56% overall yield (141 mg, 0.62 mmol). The first fraction proved

to be a mixture of two pairs of major enantiomers in a ratio of

70:30 (120 mg, 0.53 mmol, 50%). The second fraction was found

to be a complex mixture of four pairs of enantiomers and purified

once more to afford two pairs of major enantiomers (14 mg,

0.06 mmol, 6%) and two pairs of minor enantiomers in a ratio of

65:35 (7 mg, 0.03 mmol, 3%). Two pairs of major enantiomers

(70:30 ratio, 56%): R_f(hexane/EtOAc, 90:10) = 0.47. IR (KBr film):

3

H), 1.38 (t, ³J_H8,H7= 7.1 Hz, 3 H, 8-H), 1.38 (t, J_H8Ј,H7Ј= 7.1 Hz,

3

3 H, 8Ј-H), 1.20 (d, J_H9,H4= 6.1 Hz, 3 H, 9-H), 1.19 (d,

³J_{H9Ј,H4Ј,obs.}≈ 6.4 Hz, 3 H, 9Ј-H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 298 K): δ = 224.2, 224.0 (C-6, C-6Ј), 135.1 (C-11, C-11Ј),

116.5 (C-12, C-12Ј), 81.9, 81.1 (C-1, C-1Ј), 75.4, 74.8 (C-4, C-4Ј),

67.8 (C-7, C-7Ј), 61.7, 61.4 (C-5, C-5Ј), 35.8, 35.5 (C-3, C-3Ј), 33.5,

32.5 (C-2, C-2Ј), 30.0, 29.1 (C-10, C-10Ј), 21.5, 21.1 (C-9, C-9Ј),

13.6 (C-8, C-8Ј) ppm. MS (APCI⁺): m/z (%) = 229.9 (12)

[M + H]⁺, 229.0 (100) [M]⁺, 193.2 (7), 183 (7).

O-Ethyl 2-Methyl-2-(5-methyltetrahydrofuran-2-yl)pent-4-enethio-

ate (21): A solution of thione ester 18 (210 mg, 1.04 mmol) in dry

THF (2 mL) was added dropwise to a solution of tBuOK

ν = 3076 (vw), 2974 (vs), 2870 (m), 1639 (v; traces of ester), 1444 (185.5 mg, 1.65 mmol) in dry THF (4 mL) under argon at –78 °C

˜

(m), 1386 (m), 1292 (m), 1251 (vs), 1193 (s), 1165 (s), 1145 (w), over a period of 25 min. The reaction mixture was stirred at –78 °C

1092 (vs), 1017 (s), 973 (vw), 915 (m), 860 (vw) cm^–1. ¹H NMR

for 45 min, and then allyl iodide (0.15 mL, 1.66 mmol) was added

dropwise. The resulting mixture was allowed to reach –30 °C. The

3

(400 MHz, CDCl₃, 298 K):

δ

=

5.84–5.74 (m, J_H11,H12b

=

3

³J_H11Ј,H12bЈ= 17.0, J_H11,H12a= J_H11Ј,H12aЈ= 10.2 Hz, 2 H, 11-H, acetone/N₂cooling bath was removed, and the reaction mixture

3

11Ј-H), 5.00 (≈dq, J_H12b,H11

=

³J_H12bЈ,H11Ј= 17.0, J_H12b,H12a

=

was treated with a saturated aqueous NH₄Cl solution (13 mL) and

3

³J_{H12bЈ,H12aЈ}≈ J_H12b,H10= J_{H12bЈ,H10bЈ,obs.}≈ 1.5 Hz, 2 H, 12b-H, then extracted with Et₂O (3ϫ15 mL). The combined organic layers

3

2

12bЈ-H), 4.94 (dd, J_H12a,H11

=

³J_H12aЈ,H11Ј= 10.2, J_H12a,H12b

=

were washed with brine (15 mL) and dried with anhydrous Na₂SO₄.

After filtration, the solvent was removed in vacuo, and the residue

was purified by chromatography on silica gel (eluting with a gradi-

²J_{H12aЈ,H12bЈ,obs.}≈ 1.0 Hz, 2 H, 12a-H, 12aЈ-H), 4.50 (q, J_H7,H8

3

³J_H7Ј,H8Ј= 7.1 Hz, 4 H, 7-H, 7Ј-H), 4.14 (dt, J_H1Ј,H5Ј= 9.0,

3

³J_{H1Ј,H2Ј,obs.}= 6.7 Hz, 1 H, 1Ј-H), 4.03 (dt, J_H1,H5= 8.2, ent solvent system of hexane/EtOAc from 100:0 to 95:5) to give the

3

³J_H1,H2,obs.= 6.0 Hz, 1 H, 1-H), 4.04–3.94 (m, J_obs.= 6.1 Hz, 2 H,

4Ј-H, 4-H), 2.94–2.86 (m, 2 H, 5-H, 5Ј-H), 2.72–2.66 (m, 2 H, 3a-

H, 3aЈ-H), 2.54–2.46 (m, 2 H, 3b-H, 3bЈ-H), 2.04–1.83 (m, 4 H,

title compound 21 as a yellow oil as a mixture of two isomers (21a/

21b, 87:13) in 85% overall yield (212 mg, 0.84 mmol). The thione

ester 21 was used in the next step without further purification. R_f

2a-H, 2aЈ-H, 10a-H, 10aЈ-H), 1.75–1.62 (m, 2 H, 10b-H, 10bЈ-H), (hexane/EtOAc, 90:10) = 0.50 (isomer 1, cis-21a), 0.46 (isomer 1,

3

1.48–1.39 (m, 2 H, 2b-H, 2bЈ-H), 1.37 (t, J_H8,H7

=

³J_H8Ј,H7Ј

=

trans-21b). GC (temp. progr. 2): t_R= 9.04 (isomer 1, cis-21a, 87%),

3

7.1 Hz, 6 H, 8-H, 8Ј-H), 1.21 (d, J_H9,H4= 6.1 Hz, 3 H, 9-H), 1.20

9.12 min (isomer 1, trans-21b, 13%). IR (KBr film): ν = 3076 (w),

˜

(d, J_H9Ј,H4Ј= 6.1 Hz, 3 H, 9Ј-H) ppm. ¹³C NMR (100 MHz,

2975 (vs), 1733 (w; traces of ester), 1639 (w), 1458 (m), 1387 (m),

3

CDCl₃, 298 K): δ = 223.5, 223.5 (C-6, C-6Ј), 135.5 (C-11, C-11Ј), 1291 (m), 1252 (vs), 1193 (s), 1166 (s), 1145 (s), 1092 (vs), 1016 (s),

116.2, 116.1 (C-12, C-12Ј), 81.3, 81.1 (C-1, C-1Ј), 75.7, 75.0 (C-4,

915 (s), 722 (vw), 620 (vw) cm^–1. cis-21a: ¹H NMR (400 MHz,

C-4Ј), 67.6 (C-7, C-7Ј), 62.3, 62.0 (C-5, C-5Ј), 37.1, 37.0 (C-3, C- CDCl₃, 298 K): δ = 5.70 (dddd, ³J_H12,H13b= 17.0, ³J_H12,H13a= 10.1,

4656

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4642–4661

Alkylation of Model Compounds of Nonactic Acids

3

³J_H12,H11b= 8.1, J_H12,H11a= 6.8 Hz, 1 H, 12-H), 5.03 (ddt,

³J_H13b,H12= 17.0, ²J_H13b,H13a= 2.3, ⁴J_{H13b,H11b and H11a,obs.}≈ 1.3 Hz,

3

2

1 H, 13b-H), 5.00 (ddt, J_H13a,H12= 10.1, J_H13a,H13b= 2.3,

⁴J_{H13a,H11b and H11a}= 1.0 Hz, 1 H, 13a-H), 4.53 (dq, J_H7a,H7b

=

2

3

2

11.1, J_H7a,H8= 7.1 Hz, 1 H, 7a-H), 4.50 (dq, J_H7b,H7a= 11.1,

Ethyl 9-Hydroxy-2-methyl-2-(5-methylfuran-2-yl)non-4-enoate (25):

Under argon, CH₂Cl₂was degassed with argon bubbling for

40 min. A solution of Grubbs I catalyst (74 mg, 0.09 mmol) in de-

gassed CH₂Cl₂(2 mL) was added dropwise to a solution of 24^[72]

(200 mg, 0.90 mmol) and 22 (0.17 mL, 1.45 mmol) in degassed

CH₂Cl₂(2 mL) under argon. The reaction mixture was heated at

reflux for 5 h, and the progress of the reaction was monitored by

TLC. Then further Grubbs I catalyst (20 mg, 0.02 mmol) was

added, and the resulting mixture was heated at reflux for another

17 h. Removal of solvent gave an oily residue, which was purified

by chromatography on silica gel (from hexane gradually to hexane/

EtOAc, 75:25) to afford the title compound 25 as a mixture of two

isomers [(E)/(Z) = 65:35] in 81% overall yield (215 mg, 0.73 mmol).

R_f(hexane/EtOAc, 75:25) = 0.10. ¹H NMR (400 MHz, CDCl₃,

³J_H7b,H8= 7.1 Hz, 1 H, 7b-H), 4.26 (≈dd, J_H1,H2a= 6.8, J_H1,H2b

3

≈ 8.0 Hz, 1 H, 1-H), 3.97 (dquint, ³J_H4,H3a= 8.2, ³J_H4,H9= ³J_H4,H3b

2

3

= 6.0 Hz, 1 H, 4-H), 2.72 (m, J_H11a,H11b= 13.5, J_H11a,H12

=

2

3

6.8 Hz, 1 H, 11a-H), 2.45 (≈ddt, J_H11b,H11a= 13.5, J_H11b,H12

8.1, ⁴J_{H11b,H13a and H13b}= 1.0 Hz, 1 H, 11b-H), 1.93 (dddd, ²J_H3b,H3a

= 11.8, ³J_H3b,H2b= 8.4, ³J_H3b,H4= 6.0, ³J_H3b,H2a= 4.7 Hz, 1 H, 3b-

2

3

H), 1.81 (≈ddt, J_H2b,H2a= 12.8, J_H2b,H3b= 8.4, J_H2b,H1

≈

³J_H2b,H3a≈ 8.0 Hz, 1 H, 2b-H), 1.69 (dddd, J_H2a,H2b= 12.8,

³J_H2a,H3a= 9.3, ³J_H2a,H1= 6.8, ³J_H2a,H3b= 4.7 Hz, 1 H, 2a-H), 1.40

2

3

2

(t, J_H8,H7= 7.1 Hz, 3 H, 8-H), 1.34 (≈ddt, J_H3a,H3b= 11.8,

3

³J_H3a,H2a= 9.3, J_H3a,H4≈ J_H3a,H2b≈ 8.0 Hz, 1 H, 3a-H), 1.24 (d,

³J_H9,H4= 6.0 Hz, 3 H, 9-H), 1.21 (s, 3 H, 10-H) ppm. ¹³C NMR

(100 MHz, CDCl₃, 298 K): δ = 226.3 (C-6), 134.3 (C-12), 117.4 (C-

13), 84.3 (C-1), 75.5 (C-4), 68.0 (C-7), 57.6 (C-5), 44.4 (C-11), 33.4

(C-3), 27.0 (C-2), 20.7 (C-9), 17.5 (C-10), 13.5 (C-8) ppm. MS (EI,

70 eV): m/z (%) = 244.17 (2) [M + 2H]⁺, 243.13 (17) [M + H]⁺,

227.09 (32) [M – CH₃]⁺, 213.14 (60) [M – CH₂–CH₃]⁺, 169.12 (22),

157.09 (34), 155.10 (100), 153.22 (50), 129.12 (28), 85.18 (42), 67.11

(85). trans-21b: MS (EI, 70 eV): m/z (%) = 244.17 (6) [M + 2H]⁺,

243.07 (34) [M + H]⁺, 227.12 (32) [M – CH₃]⁺, 213.08 (55) [M –

CH₂–CH₃]⁺, 169.21 (22), 158.21 (40), 155.09 (81), 153.16 (46),

129.16 (33), 111.12 (26), 85.20 (55), 67.11 (100). HRMS: calcd. for

[C₁₃H₂₂O₂SNa]⁺265.12382; found 265.12389.

3

298 K): δ = 6.02 (d, J_H2Ј,H3Ј= 3.1 Hz, 2 H, 2Ј-H), 6.00 (d, J_H2,H3

3

4

= 3.1 Hz, 1 H, 2-H), 5.88 (dq, J_H3Ј,H2Ј= 3.1, J_H3Ј,H9Ј= 1.0 Hz, 1

H, 3Ј-H), 5.87 (dq, ³J_H3,H2= 3.1, ⁴J_H3,H9= 1.0 Hz, 1 H, 3-H), 5.46

3

(dtm, J_H13,H12= 15.1, J_H13,H14= 6.9 Hz, 1 H, 13-H), 5.49–5.43

(m, 1 H, 13Ј-H), 5.28–5.18 (m, ³J_H12,H13= 15.1 Hz, 2 H, 12-H, 12Ј-

2

3

H), 4.09 (dq, J_H7a,H7b= 11.2, J_H7a,H8= 7.1 Hz, 1 H, 7a-H), 4.10

3

(m, J_H7b,H8= 7.1 Hz, 1 H, 7b-H), 4.18–4.05 (m, J_H7aЈ,H8Ј

=

³J_H7bЈ,H8Ј= 7.1 Hz, 2 H, 7aЈ-H, 7bЈ-H), 3.62 (t, J_{H17Ј,H16Ј,obs.}

3

6.5 Hz, 3 H, 17Ј-H), 3.59 (t, J_H17,H16,obs.= 6.5 Hz, 3 H, 17-H),

2

2.76–2.61 (m,

2 H, 11Ј-H), 2.67 (≈dd, J_H11a,H11b= 12.8,

2

³J_{H11a,H12,obs.}≈ 7.4 Hz, 1 H, 11a-H), 2.55 (ddd, J_H11b,H11a= 12.8,

³J_H11b,H12= 7.0, J_{H11b,H13,obs.}= 1.0 Hz, 1 H, 11b-H), 2.24 (d,

4

³J_H9,H3= J_H9Ј,H3Ј= 1.0 Hz, 6 H, 9-H, 9Ј-H), 2.07–1.99 (m, 1 H,

3

14Ј-H), 1.98 (≈q, J_H14,H15,obs.

=

³J_H14,H13= 6.9 Hz, 14-H), 1.73

(br., 2 H, OH), 1.65–1.34 (m, 8 H, 15-H, 16-H, 15Ј-H, 16Ј-H), 1.45

3

(s, 3 H, 10Ј-H), 1.43 (s, 3 H, 10-H), 1.20 (t, J_H8Ј,H7Ј= 7.1 Hz, 3

3

H, 8Ј-H), 1.20 (t, J_H8,H7= 7.1 Hz, 3 H, 8-H) ppm. ¹³C NMR

(100 MHz, CDCl₃, 298 K): δ = 174.2, 174.1 (C-6, C-6Ј), 154.6,

154.4 (C-1, C-1Ј), 151.1, 151.0 (C-4, C-4Ј), 134.2, 132.6 (C-13, C-

13Ј), 125.0, 124.3 (C-12, C-12Ј), 106.3, 106.1 (C-2, C-2Ј), 105.8,

105.7 (C-3, C-3Ј), 62.6 (C-17, C-17Ј), 60.9, 60.8 (C-7, C-7Ј), 47.1,

47.0 (C-5, C-5Ј), 40.3 (C-11), 34.7 (C-11Ј), 34.6, 26.9 (C-14, C-14Ј),

32.2, 32.1 (C-16, C-16Ј), 25.6, 25.4 (C-15, C-15Ј), 20.9, 20.8 (C-10,

C-10Ј), 14.1, 14.0 (C-8, C-8Ј), 13.5 (C-9, C-9Ј) ppm. MS (APCI⁺):

m/z (%) = 295.9 (17) [M + 2 H]⁺, 295.0 (100) [M + H]⁺, 221.10

(13).

Olefin (Alkene) Metathesis Reactions

1-Hex-5-enyloxydodecane (23): Hex-5-enol (22; 0.6 mL, 5.0 mmol)

was added dropwise to a suspension of NaH (100%, 180 mg,

7.5 mmol) in DMF (over molecular sieves, 6 mL) under argon at

5 °C over a period of 5 min. The reaction mixture was allowed to

reach room temperature, after which time stirring was continued

for 2 h. Dodecyl bromide (1.45 mL, 6.0 mmol) was added dropwise,

and the resulting mixture was stirred for 3.5 h and then diluted

with Et₂O (10 mL). Water (10 mL) was added portionwise, the lay-

ers were separated, and the aqueous layer was extracted with Et₂O

(2ϫ10 mL). The combined organic layers were washed with brine

(10 mL) and dried with anhydrous MgSO₄. After filtration, the sol-

vent was removed in vacuo, and the residue was purified by

chromatography on silica gel (hexane/EtOAc, 98:2) to give the title

compound 23 as a yellow oil (525 mg, 1.96 mmol, 40%). R_f(hex-

ane/EtOAc, 98:2) = 0.09. ¹H NMR (400 MHz, CDCl₃, 298 K): δ =

3

5.80 (ddt, J_H5,H6b= 17.0, J_H5,H6a= 10.2, J_H5,H4= 6.7 Hz, 1 H,

5-H), 5.00 (dm, ³J_H6b,H5= 17.0 Hz, 1 H, 6b-H), 4.94 (dm, ³J_H6a,H5

= 10.2 Hz, 1 H, 6a-H), 3.40 and 3.38 (t, J = 6.6, 6.7 Hz, 2ϫ2 H,

3

1-H, 7-H), 2.06 (≈qm, J_H4,H5,obs.

≈

³J_H4,H3,obs.≈ 7.1 Hz, 2 H, 4-

H), 1.61–1.51 (m, 4 H, 2 CH₂), 1.47–1.41 (m, 2 H, 3-H), 1.35–1.20 Ethyl

9-Dodecyloxy-2-methyl-2-(5-methylfuran-2-yl)non-4-enoate

(28) and Diethyl 2,7-Dimethyl-2,7-bis(5-methylfuran-2-yl)oct-4-en-

¹³C NMR (100 MHz, CDCl₃, 298 K): δ = 138.8 (C-5), 114.4 (C-6), edioate (27): According to the procedure reported for the synthesis

3

(m, 18 H, 9 CH₂), 0.88 (t, J_H18,H17,obs.= 7.2 Hz, 3 H, 18-H) ppm.

71.0, 70.7 (C-1, C-7), 33.6 (C-4), 31.9 to 22.7 (12 C): 31.9, 29.8,

29.7, 29.6 (3 C), 29.5, 29.3, 29.2, 26.1, 25.5, 22.7, 14.1 (C-18) ppm.

MS (APCI⁺): m/z (%) = 269.1 (100) [M + H]⁺.

of compound 25, ester 24 (135 mg, 0.61 mmol), olefin 23 (0.36 g,

0.81 mmol) and Grubbs I catalyst (69 mg, 0.08 mmol) reacted to

give compounds 28 in 54% overall yield and 29 in 21% overall

Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

4657

F. Loiseau, I. Kholod, R. Neier

FULL PAPER

yield as an inseparable mixture in the first and second fractions

and the self-coupling product 27 (21 mg, 0.05 mmol, 8%) in the

third fraction after chromatography on silica gel (from hexane

gradually to hexane/EtOAc, 90:10). The first fraction (155 mg, 28/

29, 64:36) corresponds to 28 (0.20 mmol, 33%) and 29 (0.11 mmol,

18%). The second fraction (74 mg, 28/29, 84:66) corresponds to 28

(0.13 mmol, 21%) and 29 (0.02 mmol, 3%). 27: R_f(hexane/EtOAc,

(C-8, C-8Ј, C-29, C-29Ј), 13.6 (C-9, C-9Ј) ppm. MS (APCI⁺): m/z

(%) = 464.1 (29) [M + 2 H]⁺, 463.2 (100) [M + H]⁺, 389.3 (8) [M –

73 (CO₂Et)]⁺. HRMS: calcd. for [C₂₉H₅₀O₄Na]⁺485.36068; found

485.35940.

95:5) = 0.19. IR (KBr film): ν = 2982 (m), 2937 (m), 1732 (vs),

˜

1610 (vw), 1561 (w), 1452 (w), 3063 (vw), 1376 (vw), 1235 (s), 1144

(m), 1098 (s), 1023 (s), 964 (vw), 964 (vw), 942 (w), 859 (vw), 783

(m) cm^–1. ¹H NMR (400 MHz, CDCl₃, 298 K): δ = 6.01 (d,

3

³J_H2Ј,H3Ј= 3.1 Hz, 2 H, 2Ј-H), 5.97, 5.96 (2 d, J_H2,H3= 3.1,

3

³J_H17,H18= 3.1 Hz, 2 H, 2-H, 17-H), 5.87, 5.86 (2 dq, J_H3Ј,H2Ј

=

4

3

4

3.1, J_H3Ј,H9Ј= 1.1, J_H3,H2

= 1.1 Hz, 2ϫ2 H, 3Ј-H, 3-H, 18-H), 5.33–5.28 (m, 4 H, 12-H, 13-

=

³J_H18,H17= 3.1, J_H3,H9= J_H18,H23

3

H, 12Ј-H), 4.11, 4.13 (2 q, J_H7Ј,H8Ј= 7.1, J_H7,H8

= =

³J_H21,H22

7.1 Hz, 2ϫ4 H, 7Ј-H, 7-H, 21-H), 5.75–5.55 (m, 8 H, 11-H, 14-H,

11Ј-H), 2.25, 2.24 (2 d, ³J_H9Ј,H3Ј= 1.1, ³J_H9,H3= ³J_H23,H18= 1.1 Hz,

2ϫ6 H, 9Ј-H, 9-H, 23-H), 1.44 (s, 6 H, 10Ј-H), 1.39, 1.40 (s, 6 H,

3

10-H, 24-H), 1.21, 1.20 (2 t, J_H8Ј,H7Ј= 7.1, J_H8,H7= J_H22,H21

=

7.1 Hz, 2ϫ6 H, 8Ј-H, 8-H, 22-H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 298 K): δ = 174.1, 174.0, 173.9 (C-6, C-20, C-6Ј), 154.5,

154.4, 154.3 (C-1, C-16, C-1Ј), 151.2, 1551.1 (C-4, C-19, C-4Ј),

129.0, 127.3 (C-12, C-13, C-12Ј), 106.4, 106.3, 106.2 (C-2, C-17, C-

2Ј), 105.9, 105.8 (C-3, C-18, C-3Ј), 61.0, 60.9 (C-7, C-21, C-7Ј),

47.0 (C-5, C-15, C-5Ј), 40.3, 34.8 (C-11, C-14, C-11Ј), 20.9, 20.8

(C-10, C-24, C-10Ј), 14.1 (C-8, C-22, C-8Ј), 13.6 (C-9, C-23, C-9Ј)

ppm. MS (APCI⁺): m/z (%) = 418.0 (25) [M + 2 H]⁺, 417.0 (100)

[M + H]⁺, 359.1 (13) [M – 57]⁺, 343.1 (16) [M – 73 (CO₂Et)]⁺.

HRMS: calcd. for [C₂₄H₃₂O₆Na]⁺439.20966; found 439.20900. 28:

Ethyl 9-Dodecyloxy-2-methyl-2-(5-methyltetrahydrofuran-2-yl)non-

4-enoate (30) and Ethyl (E)-2-Methyl-2-(5-methyltetrahydrofuran-2-

yl)-5-phenylpent-4-enoate (31): Under argon, ClCH₂CH₂Cl (7 mL)

was degassed with argon bubbling for 40 min. A solution of

Grubbs I catalyst (42 mg, 0.05 mmol) in degassed ClCH₂CH₂Cl

(1.5 mL) was added dropwise to a solution of 12 (cis-12a/trans-12c,

90:10, 116 mg, 0.51 mmol) and 23 (165 mg, 0.62 mmol) in degassed

ClCH₂CH₂Cl (1.5 mL) under argon at 20 °C. The reaction mixture

was heated at reflux for 5 h, and the progress of the reaction was

monitored by TLC. Then, further Grubbs I catalyst (17 mg,

0.02 mmol) was added, and the resulting mixture was heated at

reflux for another 15 h. The presence of starting materials was ob-

served by TLC. Thus, more 23 (20 mg, 0.08 mmol) and Grubbs I

catalyst (20 mg, 0.02 mmol) were added. The reaction mixture was

heated at reflux again for another 21 h, and the presence of starting

materials was detected by TLC. Again, even more 23 (20 mg,

0.08 mmol) and Grubbs I catalyst (20 mg, 0.02 mmol) were added,

and the resulting solution was heated at reflux for a further 21 h.

Removal of the solvent gave an oily residue, which was purified by

chromatography on silica gel (from hexane gradually to hexane/

Et₂O, 95:5) to give four fractions. The first fraction proved to be a

complex mixture (45 mg, 12/29/32, 10:40:50) corresponding to 23

(4.5 mg, 0.02 mmol, 3%), 29 (18 mg, 0.04 mmol, 7%) and 32

(22.5 mg, 0.07 mmol, 13%). The second fraction contained 29

(90 mg, 0.18 mmol, 35%). The third fraction was found to be a

complex mixture (47 mg, 12/30, 60:40) corresponding to 12

(28.2 mg, 0.13 mmol, 24%) and 30 (18.8 mg, 0.04 mmol, 8%). The

fourth fraction showed a complex mixture (106.1 mg, 30/31, 85:15)

corresponding to 30 (90.2 mg, 0.193 mmol, 38%) and 31 (15.9 mg,

0.053 mmol, 10%). Fourth fraction (30/31, 85:15): R_f(hexane/Et₂O,

(E)/(Z) = 65:35. R (hexane/EtOAc, 95:5) = 0.30. IR (KBr film): ν

˜

f

= 2926 (vs), 2854 (vs), 1735 (vs), 1562 (vw), 1460 (w), 1376 (w),

1

1234 (m), 1115 (s), 1023 (m), 970 (w), 780 (w), 722 (vw) cm^–1. H

3

NMR (400 MHz, CDCl₃, 298 K): δ = 6.02 (d, J_H2Ј,H3Ј= 3.1 Hz,

3

1 H, 2Ј-H), 6.00 (d, J_H2,H3= 3.1 Hz, 1 H, 2-H), 5.88–5.86 (m, 1

H, 3Ј-H), 5.86 (dq, ³J_H3,H2= 3.1, ⁴J_H3,H9= 1.0 Hz, 1 H, 3-H), 5.48

2

3

(≈dtm, J_H13,H12≈ 15.0, J_H13,H14≈ 7.0 Hz, 1 H, 12-H), 5.50–5.43

2

(m,

2

H, 13-H, 13Ј-H), 5.26 (≈dtm, J_H12,H13

≈ 15.0,

³J_{H12,H11a and H11b,obs.}= 7.0 Hz, 1 H, 12-H), 5.24–5.19 (m, 1 H, 12Ј-

H), 4.14 (q, J_H7Ј,H8Ј= 7.1 Hz, 2 H, 7Ј-H), 4.13 (q, J_H7,H8

7.1 Hz, 2 H, 7-H), 3.39 (t, J_H17Ј,H18Јor J_H18Ј,H17Ј= 6.8 Hz, 2 H,

17Ј-H or 18Ј-H), 3.38 (t, J_H17Ј,H18Јor J_H18Ј,H17Ј= 6.7 Hz, 2 H,

3

=

3

17Ј-H or 18Ј-H), 3.37 (t, J_H17,H18or J_H18,H17= 6.8 Hz, 2 H, 17-

2

3

H or 18-H), 2.76 (≈ddd, J_{H11aЈ,H11bЈ}≈ 14.5, J_{H11aЈ,H12Ј,obs.}≈ 7.6,

⁴J_{H11aЈ,H13Ј,obs.}= 1.4 Hz, 1 H, 11aЈ-H), 2.70 (≈ddd, J_H11a,H11b

≈

2

3

4

13.7, J_{H11a,H12,obs.}≈ 7.6, J_{H11a,H13,obs.}= 0.8 Hz, 1 H, 11b-H),

2

2.70–2.64 (m, J_{H11bЈ,H11aЈ}≈ 14.5 Hz, 1 H, 11bЈ-H), 2.58 (ddd,

²J_H11b,H11a= 13.7, J_H11b,H12= 7.0, J_{H11b,H13,obs.}= 1.0 Hz, 1 H,

3

4

11b-H), 2.25 (d, ⁴J_H9,H3= ⁴J_H9Ј,H3Ј= 1.0 Hz, 6 H, 9-H, 9Ј-H), 2.07

(≈q, J_{H14Ј,H13Ј,obs.}≈ ³J_{H14Ј,H15Ј,obs.}≈ 7.3 Hz, 2 H, 14Ј-H), 2.00 (≈q,

3

³J_H14,H13,obs.

≈

³J_H14,H15,obs.≈ 7.0 Hz, 2 H, 14-H), 1.64–1.51 (m,

³J_obs.= 6.8 Hz, 8 H, 16Ј-H, 19Ј-H, 16-H, 19-H), 1.44–1.24 (m, 40

H, 15-H, 15Ј-H, 20-H to 28-H, 20Ј-H to 28Ј-H), 1.46 (s, 3 H, 10Ј-

H), 1.44 (s, 3 H, 10-H), 1.21 (t, ³J_H8Ј,H7Ј= 7.1 Hz, 3 H, 8Ј-H), 1.21

3

(t, J_H8,H7= 7.1 Hz, 3 H, 8-H), 0.88 (t, J_H29,H28= J_{H29Ј,H28Ј,obs.}

≈ 6.8 Hz, 6 H, 29-H, 29Ј-H) ppm. ¹³C NMR (100 MHz, CDCl₃,

298 K): δ = 174.1 (C-6, C-6Ј), 154.7, 154.5 (C-1, C-1Ј), 151.1, 151.0

(C-4, C-4Ј), 134.4, 134.8 (C-13, C-13Ј), 124.9, 124.2 (C-12, C-12Ј),

106.3, 106.1 (C-2, C-2Ј), 105.9, 105.8 (C-3, C-3Ј), 71.0, 70.9, 70.7

(C-17, C-17Ј, C-18, C-18Ј), 60.9, 60.8 (C-8, C-8Ј), 47.2, 47.1 (C-5,

C-5Ј), 40.4 (C-11, C-11Ј), 31.9, 26.2 (C-14, C-14Ј), 32.4, 29.8, 29.6,

29.6, 29.5, 29.4, 29.3, 29.2, 26.2, 26.0, 22.7 (C-15, C-15Ј, C-16, C-

16Ј, C-19 to C-28, C-19Ј to C-28Ј), 21.0, 20.9 (C-10, C-10Ј), 14.1

90:10) = 0.18. IR (KBr film): ν = 2927 (vs), 2854 (s), 1732 (s), 1465

˜

(m), 1378 (w), 1292 (w), 1179 (m), 1116 (s), 1095 (s), 1024 (m), 970

(w), 835 (s), 859 (vw), 722 (vw) cm^–1. 30 [(E)/(Z) = 75:25]. (E)-30:

¹H NMR (400 MHz, CDCl₃, 298 K): δ = 5.44 (dt, ³J_H13,H12= 15.0,

3

³J_H13,H14,obs.= 6.6 Hz, 1 H, 13-H), 5.31 (ddd, J_H12,H13= 15.0,

³J_H12,H11b= 7.9, ³J_H12,H11a= 6.8 Hz, 1 H, 12-H), 4.12 (dq, ²J_H7a,H7b

4658

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4642–4661

Alkylation of Model Compounds of Nonactic Acids

3

2

3

= 11.4, J_H7a,H8= 7.1 Hz, 1 H, 7a-H), 4.11 (dq, J_H7b,H7a= 11.4,

system, partially resolved, J_H21,H20= 9.0 Hz, 2 H, 21-H), 6.67

³J_H7b,H8= 7.1 Hz, 1 H, 7b-H), 4.02 (≈dd, J_H1,H2a= 7.1, (AAЈBBЈ system, partially resolved, J_H20,H21= 9.0 Hz, 2 H, 20-

3

³J_H1,H2b,obs.≈ 7.5 Hz, 1 H, 1-H), 3.94 (dquint, J_H4,H3a= 7.8, H), 3.91 (t, J_H1,H2= 6.6 Hz, 2 H, 1-H), 1.80–1.73 (m, 2 H, 2-H),

3

³J_H4,H9= ³J_H4,H3b= 6.0 Hz, 1 H, 4-H), 3.40–3.35 (m, J_H17,H16,obs.

1.46–1.20 (m, 30 H, 3-H to 17-H), 0.89 (≈t, J_H18,H17,obs.= 6.8 Hz,

3

=

³J_H18,H19,obs.= 6.7 Hz, 4 H, 17-H, 18-H), 2.51–2.41 (m, 2 H, 18-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K): δ = 159.0

²J_H11a,H11b= 13.6, J_H11a,H12= 6.8 Hz, 1 H, 11a-H), 2.25–2.17 (m,

(C-19), 138.1 (2 C, C-21), 116.9 (2 C, C-20), 82.4 (C-22), 68.1 (C-

3

²J_H11b,H11a= 13.6, J_H11b,H12= 7.9 Hz, 1 H, 11b-H), 2.10–1.88 (m, 1), 31.9 (C-16), 29.7–29.1 (13 C, C-2, C-4 to C-15), 26.0 (C-3), 22.7

3

³J_H3b,H4= 6.0, J_H3b,H2a= 5.0 Hz, 3 H, 3b-H, 14-H), 1.83 (≈ddt,

(C-17), 14.1 (C-18) ppm. MS (ESI⁺): m/z (%) = 473.1. (100) [M +

3

²J_H2b,H2a= 12.3, J_H2b,H3b,obs.= 8.5, J_H2b,H1≈ J_H2b,H3a≈ 7.8 Hz,

H]⁺.

3

2

3

1 H, 2b-H), 1.72 (dddd, J_H2a,H2b= 12.3, J_H2a,H3a= 9.3, J_H2a,H1

= 7.1, ³J_H2a,H3b= 5.0 Hz, 1 H, 2a-H), 1.64–1.51 (m, 4 H, 16-H, 19-

H), 1.41–0.91 (m, ³J_H3a,H2a= 9.3, J_H3a,H4≈ ³J_H3a,H2b≈ 7.8 Hz, 21

3

H, 3a-H, 15-H, 20-H to 28-H), 1.23 (t, J_H8,H7= 7.1 Hz, 3 H, 8-

3

H), 1.20 (d, J_H9,H4= 6.0 Hz, 3 H, 9-H), 1.07 (s, 3 H, 10-H), 0.87

(≈t, J_H29,H28= 6.8 Hz, 3 H, 29-H) ppm. ¹³C NMR (100 MHz,

3

Ethyl (E)-2-Methyl-2-(5-methylfuran-2-yl)-5-(4-octadecyloxyphen-

yl)pent-4-enoate (34a): Triethylamine (3.1 mL, 22.3 mmol) was

added to a solution of palladium diacetate (43 mg, 0.19 mmol) and

tri-o-tolylphosphane (128 mg, 0.42 mmol) in dry DMF (35 mL) un-

der argon at 25 °C. The reaction mixture was stirred for a few min-

utes, and a solution of ester 24 (300 mg, 1.35 mmol) in dry DMF

(10 mL) was added. Stirring was continued for 15 min, and then 1-

iodo-4-(octadecyloxy)benzene (33; 1.59 g, 3.37 mmol), dissolved by

heating in dry DMF (10 mL), was added. The resulting mixture

was heated at 90 °C for 44 h and then cooled to room temperature

and diluted with EtOAc (180 mL) and water (80 mL). The layers

were separated, and the aqueous layer was extracted with EtOAc

(70 mL). The combined organic layers were washed with brine

(70 mL) and dried with anhydrous MgSO₄. After filtration, the sol-

vent was removed in vacuo, and the residue was purified twice by

chromatography on silica gel (hexane/EtOAc gradually) to give

compound 34 as a mixture of two regioisomers (34a/34b, 90:10) in a

quantitative overall yield (780 mg, 1.38 mmol). R_f(hexane/EtOAc,

CDCl₃, 298 K): δ = 175.2 (C-6), 133.7 (C-13), 125.5 (C-12), 82.9

(C-1), 75.4 (C-4), 70.9 (C-17), 70.7 (C-18), 60.1 (C-7), 50.1 (C-5),

40.5 (C-11), 33.2 (C-3), 32.4 (C-14), 31.9 (C-27), 29.8, 29.7, 29.6,

29.5, 29.4, 29.3, 29.2 (C-16, C-19, C-21 to C-26), 27.1 (C-2), 26.2

(C-20), 26.0 (C-15), 22.7 (C-28), 20.8 (C-9), 15.8 (C-10), 14.3 (C-

8), 14.1 (C-29) ppm. MS (EI, 70 eV): m/z (%) = 466.40 (2) [M]⁺,

341.87 (3), 319.60 (4), 262.29 (13), 251.28 (22), 239.30 (35), 186.17

(100), 138.16 (60), 126.16 (85), 67.18 (87). 31 (Partial Data): ¹H

3

NMR (400 MHz, CDCl₃, 298 K): δ = 7.33–7.29 (m, J_H16,H17

=

³J_H16Ј,H17= 6.8 Hz, J_H16,H15

=

³J_H16Ј,H15Ј= 6.3 Hz, 2 H, 16-H,

16Ј-H), 7.27–7.25 (m, J_H15,H16= J_H15Ј,H16Ј= 6.3 Hz, 2 H, 15-H,

3

15Ј-H), 7.21–7.17 (m, J_H17,H16= J_H17,H16Ј= 6.8 Hz, 1 H, 17-H),

3

6.40 (d, J_H13,H12= 15.7 Hz, 1 H, 13-H), 6.14 (ddd, J_H12,H13

=

3

15.7 Hz, J_{H12,H11b,obs.}= 8.1 Hz, J_H12,H11a= 7.0 Hz, 1 H, 12-H),

1.15 (s, 3 H, 10-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K): δ

= 133.2 (C-13), 128.4 (C-16, C-16Ј), 127.0 (C-17), 126.1 (C-15, C-

15Ј), 124.8 (C-12) ppm. MS (EI, 70 eV): m/z (%) = 302.29 (10)

[M]⁺, 228.23 (10), 202.23 (15), 201.19 (100) [M – CH₂CHCHC₆H₅]⁺,

187.19 (80), 171.19 (37), 155.19 (25), 129.18 (35), 117.17 (45),

115.16 (65), 95.18 (15), 91.17 (35), 85.16 (23).

1

90:10) = 0.37. 34a: H NMR (400 MHz, CDCl₃, 298 K): δ = 7.24

3

(≈d, J_H15,H16= 7.7 Hz, 2 H, 15-H), 6.84 (≈d, J_H16,H15= 7.7 Hz,

2

2 H, 16-H), 6.39 (d, J_H13,H12= 15.7 Hz, 1 H, 13-H), 6.08 (d,

³J_H2,H3= 3.1 Hz, 1 H, 2-H), 5.87–5.94 (m, J_H3,H2= 3.1, J_H12,H13

3

2

3

= 15.7 Hz, 2 H, 3-H, 12-H), 4.15–4.22 (m, J_H7,H8= 7.1 Hz, 2 H,

7-H), 3.96 (t, ³J_H18,H19= 6.6 Hz, 2 H, 18-H), 2.91 (ddd, ²J_H11a,H11b

3

4

= 13.8, J_H11a,H12= 7.7, J_H11a,H13= 1.1 Hz, 1 H, 11a-H), 2.81

(ddd, ²J_H11b,H11a= 13.8, ³J_H11b,H12= 7.1, ⁴J_H11b,H13= 1.3 Hz, 1 H,

2

11b-H), 2.30 (d, J_H9,H3,obs.= 0.7 Hz, 3 H, 9-H), 1.83–1.73 (m,

³J_H19,H18= 6.6 Hz, 2 H, 19-H), 1.51 (s, 3 H, 10-H), 1.46–1.23 (m,

30 H, 20-H to 34-H), 1.22 (t, ³J_H8,H7= 7.1 Hz, 3 H, 8-H), 0.90 (≈t,

³J_H35,H34,obs.≈ 6.8 Hz, 3 H, 8-H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 298 K): δ = 174.0 (C-6), 158.5 (C-17), 154.5 (C-1), 151.2

(C-4), 132.8 (C-13), 130.0 (C-14), 127.2 (C-15), 122.9 (C-12), 114.4

(C-16), 106.3 (C-2), 105.9 (C-3), 68.0 (C-18), 61.0 (C-7), 47.4 (C-

5), 40.9 (C-11), 31.9, 29.7, 29.4, 29.4, 29.3, 26.0 (C-20 to C-33),

29.6 (C-19), 22.7 (C-34), 22.6, 21.1 (C-10), 14.2, 14.1 (C-35, C-8),

13.6 (C-9) ppm. HRMS: calcd. for [C₃₇H₅₈O₄Na]⁺589.42328;

1-Iodo-4-octadecyloxybenzene (33): KOH (842 mg, 15.00 mmol)

was added to a solution of 4-iodophenol (3 g, 13.63 mmol) in

EtOH (95%, 35 mL). The reaction mixture was heated at 60 °C for

10 min, and octadecyl iodide (5.7 g, 15.00 mmol) was added. Heat-

ing was then continued for 6 h. TLC showed the reaction was not

yet completed. KOH (200 mg, 3.56 mmol) was added, and the re-

sulting mixture was heated again at 60 °C for another 18 h. After

filtration through cotton cloth to remove excess octadecyl iodide,

the reaction mixture was concentrated in vacuo. The oily residue

was purified twice by chromatography on silica gel (hexane/EtOAc,

90:10) to give the title compound 33 as a white solid (3.33 g,

7.88 mmol, 58%). R_f(hexane/EtOAc, 95:5) = 0.66. IR (KBr film):

1

found 589.42292. 34b (Partial Data): H NMR (400 MHz, CDCl₃,

2

298 K): δ = 5.17 [d, J_H(Z),H(E)= 1.8 Hz, 1 H, (Z)-H], 4.92 [d,

²JH(E),H(Z) = 1.8 Hz, 1 H, (E)-H] ppm.

Ethyl

(E)-2-Methyl-2-(5-methyltetrahydrofuran-2-yl)-5-(4-octa-

decyloxyphenyl)pent-4-enoate (35a): According to the procedure re-

ported for the synthesis of compound 34a, palladium diacetate

(15.5 mg, 0.07 mmol), tri-o-tolylphosphane (45 mg, 0.15 mmol),

triethylamine (1.1 mL, 7.89 mmol), ester 12 (cis-12a/trans-12c,

90:10, 120 mg, 0.48 mmol) and 1-iodo-4-(octadecyloxy)benzene

ν = 3433 (w) (H O), 2955 (m), 2920 (vs), 2849 (vs), 1641 (vw), 1589

˜

2

(w), 1571 (w), 1489 (m), 1473 (m), 1463 (m), 1397 (vw), 1384 (w),

1285 (m), 1249 (m), 1175 (w), 1101 (vw), 1034 (vw), 1022 (vw), (33; 565 mg, 1.20 mmol) reacted to give the title compound 35

1010 (vw), 1001 (w), 828 (vw), 814 (m), 729 (vw), 719 (w), 512

(1.13 g, 5.1 mmol, 93%) after purification by chromatography on

silica gel (from hexane gradually to hexane/EtOAc, 97:3) as a mix-

(vw) cm^–1. ¹H NMR (400 MHz, CDCl₃, 298 K): δ = 7.54 (AAЈBBЈ

Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

4659

F. Loiseau, I. Kholod, R. Neier

FULL PAPER

tive assignement of the relative configuaration of 12 by chemical

correlation.

Acknowledgments

This research was supported by the Swiss National Science Foun-

dation (funding numbers 200020-104007 and 200020-112205) and

the University of Neuchatel. NMR and mass spectra were mea-

sured with instruments at the Universities of Neuchatel and Fri-

bourg acquired with the assistance of grants from the Swiss

National Science Foundation.

ture of two regioisomers (35a/35b, 90:10). Ester 35a was obtained

[1] P. Buehlmann, E. Pretsch, E. Bakker, Chem. Rev. 1998, 98,

1593–1687.

after

a second purification in 54% overall yield (148 mg,

[2] C. A. B. Garcia, L. Rover, G. D. Neto, J. Pharm. Biomed. Anal.

2003, 31, 11–18.

[3] R. Corbaz, L. Ettlinger, E. Gaumann, W. Keller Schierlein, F.

Kradolfer, L. Neipp, V. Prelog, H. Zahner, Helv. Chim. Acta

1955, 38, 1445–1448.

[4] F. Loiseau, Synthèse de derives de l’acide nonactique: etudes de

methodes pour introduire diastereoselectivement des chaînes hy-

drophobes sur la nonactine, Ph. D. Thesis, University of Neuch-

âtel, 2006, numero 1905.

[5] a) G. Solladie, X. J. Salom-Roig, G. Hanquet, Tetrahedron Lett.

2000, 41, 2737–2740; b) J. W. Jeong, B. Y. Woo, D. C. Ha, Z.

No, Synlett 2003, 393–395; c) L. Coutable, C. Saluzzo, Synthe-

sis 2008, 21, 3389–3396; d) F. Loiseau, J.-M. Simone, D. Carca-

che, P. Bobal, R. Neier, Monatsh. Chem. 2007, 138, 121–129;

e) I. Fleming, S. K. Ghosh in Studies in Natural Products

Chemistry (Ed.: Atta-ur-Rahman), Elsevier, Amsterdam, 1996,

vol. 18, pp. 229–268; B. R. Kusche, A. E. Smith, M. A.

McGuirl, N. D. Priestley, J. Am. Chem. Soc. 2009, 131, 17155–

17165; Y. D. Zhou, Q. F. Xu, H. B. Zhai, Tetrahedron Lett.

2008, 49, 5271–5272.

0.26 mmol). R (hexane/EtOAc, 90:10) = 0.34. IR (KBr film): ν =

˜

f

3031 (m), 2922 (vs), 2853 (vs), 2317 (vw), 2029 (w), 1880 (w), 1732

(vs), 1608 (vs), 1576 (m), 1511 (vs), 1468 (vs), 1386 (s), 1340 (m),

1294 (s), 1246 (vs), 1175 (vs), 1122 (vs), 1094 (vs), 1025 (vs), 967

(s), 938 (m), 900 (m), 835 (s), 802 (m), 744 (w), 722 (m), 640 (vw),

1

605 (vw), 516 (w) cm^–1. 35a: H NMR (400 MHz, CDCl₃, 298 K):

3

δ = 7.27–7.22 (m, J_H15,H16≈ 11.6 Hz, 2 H, 15-H), 6.83–6.79 (m,

3

³J_H16,H15≈ 11.6 Hz, 2 H, 16-H), 6.35 (≈d, J_H13,H12= 15.7 Hz, 1

3

H, 13-H), 5.98 (ddd, J_H12,H13= 15.7, J_H12,H11b= 8.1, J_H12,H11a

3

= 7.0 Hz, 1 H, 12-H), 4.14 (q, J_H7,H8= 7.1 Hz, 2 H, 7-H), 4.09–

3

4.06 (m, J_H1,H2a,obs.= 7.2 Hz, 1 H, 1-H), 3.97 (dquint, J_H4,H3a

=

7.9, ³J_H4,H9= J_H4,H3b= 6.0 Hz, 1 H, 4-H), 3.93 (t, J_H18,H19,obs.

3

2

3

6.7 Hz, 3 H, 18-H), 2.67 (ddd, J_H11a,H11b= 13.7, J_H11a,H12= 7.0,

⁴J_{H11a,H13,obs.}= 0.9 Hz, 1 H, 11a-H), 2.42 (ddd, ²J_H11b,H11a= 13.7,

³J_H11b,H12= 8.1, J_{H11b,H13,obs.}= 0.9 Hz, 1 H, 11b-H), 1.95 (dddd,

4

3

²J_H3b,H3a,obs.

= 11.4, J_H3b,H2b,obs.= 8.4, J_H3b,H4= 6.0,

³J_H3b,H2a,obs.= 5.0 Hz, 1 H, 3b-H), 1.90–1.81 (m, 1 H, 2b-H), 1.80–

1.72 (m, 3 H, 2a-H, 19-H), 1.63–1.16 (m, 31 H, 3a-H, 20-Hto 34-

3

[6] H. Gerlach, K. Oertle, A. Thalmann, S. Servi, Helv. Chim. Acta

1975, 58, 2036–2043.

H), 1.24 (t, J_H8,H7= 7.1 Hz, 3 H, 8-H), 1.22 (d, J_H9,H4= 6.0 Hz,

3 H, 9-H), 1.15 (s, 3 H, 10-H), 0.88 (≈t, J_H35,H34,obs.= 6.8 Hz, 3

3

[7] U. Schmidt, J. Gombos, E. Haslinger, H. Zak, Chem. Ber. 1976,

H, 35-H) ppm. ¹³C NMR (100 MHz, CDCl₃, 298 K): δ = 175.2 (C-

6), 158.4 (C-17), 132.2 (C-13), 130.2 (C-14), 127.1 (C-15, C-15Ј),

123.6 (C-12), 114.4 (C-16, C-16Ј), 82.8 (C-1), 75.5 (C-4), 67.9 (C-

18), 60.3 (C-7), 50.3 (C-5), 40.9 (C-11), 33.2 (C-3), 31.9 (C-33),

29.7, 29.6, 29.5, 29.4, 29.3, 29.2 (C-19, C-21 to C-32), 27.2 (C-2),

26.0 (C-20), 22.7 (C-34), 20.8 (C-9), 16.1 (C-10), 14.3 (C-8), 14.1

(C-35) ppm. MS (APCI⁺): m/z (%) = 572.30 (40) [M + 2 H]⁺,

571.30 (100) [M + H]⁺. HRMS: calcd. for [C₃₇H₆₂O₄SNa]⁺

593.45458; found 593.45350. 35b (Partial Data): ¹H NMR

109, 2628–2644.

[8] P. A. Bartlett, J. D. Meadows, E. Ottow, J. Am. Chem. Soc.

1984, 106, 5304–5311.

[9] J. Y. Lee, B. H. Kim, Tetrahedron 1996, 52, 571–588.

[10] I. Fleming, S. K. Ghosh, J. Chem. Soc. Perkin Trans. 1 1998,

17, 2733–2748.

[11] Y. Wu, Y.-P. Sun, Org. Lett. 2006, 8, 2831–2834.

[12] J. Nikodinovic, J. M. Dinges, S. C. Bergmeier, M. C. McMills,

D. L. Wright, N. D. Priestley, Org. Lett. 2006, 8, 443–445.

[13] J. K. Whitesell, D. Reynolds, J. Org. Chem. 1983, 48, 3548–

3551.

[14] S. Batmangherlich, A. H. Davidson, J. Chem. Soc., Chem.

Commun. 1985, 20, 1399–1401.

2

(400 MHz, CDCl₃, 298 K): δ = 5.15 [d, J_H(Z),H(E)= 1.8 Hz, 1 H,

2

(Z)-H], 5.00 [d, J_H(E),H(Z)= 1.8 Hz, 1 H, (E)-H] ppm.

[15] Y. Z. Wang, P. Metz, Tetrahedron: Asymmetry 2000, 11, 3995–

3999.

[16] J. S. Benco, H. A. Nienaber, W. G. McGimpsey, Anal. Chem.

2003, 75, 152–156.

[17] J. Chin, J. Oh, S. Y. Jon, S. H. Park, C. Walsdorff, B. Stranix,

A. Ghoussoub, S. J. Lee, H. J. Chung, S. M. Park, K. Kim, J.

Am. Chem. Soc. 2002, 124, 5374–5379.

[18] E. Pretsch, M. Badertscher, M. Welti, T. Maruizumi, W. E.

Morf, W. Simon, Pure Appl. Chem. 1988, 60, 567–574.

[19] J.-M. Simone, F. Loiseau, D. Carcache, P. Bobal, J. Jeanneret-

Gris, R. Neier, Monatsh. Chem. 2007, 138, 131–139.

[20] J.-M. Simone, F. Loiseau, D. Carcache, P. Bobal, J. Jeanneret-

Gris, R. Neier, Monatsh. Chem. 2007, 138, 141–147.

[21] M. Dobler, J. D. Dunitz, B. T. Kilbourn, Helv. Chim. Acta

1969, 52, 2573–2583.

Supporting Information (see footnote on the first page of this arti-

cle): Experimental procedures and full spectroscopical and analyti-

cal data for previously unreported compounds not included in the

Exp. Sect.; nomenclature used for the diastereoisomers of 7; tenta-

[22] M. Dobler, Helv. Chim. Acta 1972, 55, 1371–1384.

[23] M. Dobler, R. P. Phizackerley, Helv. Chim. Acta 1974, 57, 664–

674.

4660

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4642–4661

Alkylation of Model Compounds of Nonactic Acids

[24] H. Ohrui, G. H. Jones, J. G. Moffatt, M. L. Maddox, A. T. [48]

B. S. Pedersen, S. O. Lawesson, Bull. Soc. Chim. Belg. 1977, 86,

693–697.

Y. Kodama, M. Ori, T. Nishio, Helv. Chim. Acta 2005, 88, 187–

193.

T. J. Curphey, J. Org. Chem. 2002, 67, 6461–6473.

P. Metzner, R. Rakotonirina, Tetrahedron 1985, 41, 1289–1298.

S. Takano, S. Tomita, M. Takahashi, K. Ogasawara, Chem.

Lett. 1987, 7, 1379–1380.

F. Bordwell, H. E. Fried, J. Org. Chem. 1991, 56, 4218–4223.

A. Corsaro, V. Pistara, Tetrahedron 1998, 54, 15027–15062.

S. Ayral-Kaloustian, W. C. Agosta, Synth. Commun. 1981, 11,

1011–1015.

S. Iwasa, M. Yamamoto, S. Kohmoto, K. Yamada, J. Chem.

Soc. Perkin Trans. 1 1991, 5, 1173–1176.

R. Masuda, M. Hojo, T. Ichi, S. Sasano, T. Kobayashi, C. Kur-

oda, Tetrahedron Lett. 1991, 32, 1195–1198.

Y. Tsuda, Y. Sato, K. Kakimoto, K. Kanemitsu, Chem. Pharm.

Bull. 1992, 40, 1033–1036.

Christensen, S. K. Byram, J. Am. Chem. Soc. 1975, 97, 4602–

4613.

[49]

[25] T. Sato, Y. Hayakawa, R. Noyori, Bull. Chem. Soc. Jpn. 1984,

57, 2515–2525.

[50]

[51]

[52]

[26] T. Sato, R. Ito, Y. Hayakawa, R. Noyori, Tetrahedron Lett.

1978, 21, 1829–1832.

[27] T. Sato, K. Marunouchi, R. Noyori, Tetrahedron Lett. 1979,

38, 3669–3672.

[28] F. Loiseau, R. Neier, H. Stoekli-Evans, Acta Crystallogr., Sect.

E 2006, 62, 3407–3409.

[29] U. Schmidt, J. Werner, Synthesis 1986, 12, 986–992.

[30] U. Schmidt, J. Werner, J. Chem. Soc., Chem. Commun. 1986,

996–998.

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[31] T. L. Amyes, A. J. Kirby, J. Am. Chem. Soc. 1988, 110, 6505–

6514.

[32] D. A. Evans, J. S. Tedrow, J. T. Shaw, C. W. Downey, J. Am.

Chem. Soc. 2002, 124, 392–393.

[33] D. Seebach, Angew. Chem. Int. Ed. Engl. 1988, 27, 1624–1654.

[34] N. Soldermann, J. Velker, O. Vallat, H. Stoeckli-Evans, R. Ne-

ier, Helv. Chim. Acta 2000, 83, 2266–2276.

[35] N. Soldermann, J. Velker, A. Neels, H. Stoeckli-Evans, R. Ne-

ier, Synthesis 2007, 996–998.

C. J. Salomon, G. O. Danelon, O. A. Mascaretti, J. Org. Chem.

2000, 65, 9220–9222.

J. L. Herisson, Y. Chauvin, N. H. Phung, G. Lefebvre, C. R.

Hebd. Seances Acad. Sci., Ser. C 1969, 269, 661–664.

A. Michrowska, R. Bujok, S. Harutyunyan, V. Sashuk, G. Dol-

gonos, K. Grela, J. Am. Chem. Soc. 2004, 126, 9318–9325.

R. H. Grubbs, S. Chang, Tetrahedron 1998, 54, 4413–4450.

O. Brummer, A. Ruckert, S. Blechert, Chem. Eur. J. 1997, 3,

441–446.

Y. Masaki, T. Miura, M. Ochiai, Bull. Chem. Soc. Jpn. 1996,

69, 195–205.

F. D. Toste, A. K. Chatterjee, R. H. Grubbs, Pure Appl. Chem.

2002, 74, 7–10.

J. S. Kingsbury, J. P. A. Harrity, P. J. Bonitatebus, A. H. Hov-

eyda, J. Am. Chem. Soc. 1999, 121, 791–799.

T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jpn. 1971,

44, 581.

R. F. Heck, J. P. Nolley, J. Org. Chem. 1972, 37, 2320–2322.

A. Jutand, Pure Appl. Chem. 2004, 76, 565–576.

[36] Z. M. Spavold, J. A. Robinson, J. Chem. Soc., Chem. Commun.

1988, 4–6.

[37] A. J. Woo, W. R. Strohl, N. D. Priestley, Antimicrob. Agents

Chemother. 1999, 43, 1662–1668.

[62]

[63]

[38] R. J. Walczak, M. E. Nelson, N. D. Priestley, J. Am. Chem. Soc.

2001, 123, 10415–10416.

[64]

[65]

[66]

[67]

[39] M. E. Nelson, N. D. Priestley, J. Am. Chem. Soc. 2002, 124,

2894–2902.

[40] B. R. Kusche, J. B. Phillips, N. D. Priestley, Bioorg. Med. Chem.

Lett. 2009, 19, 1233–1235.

[41] E. J. Corey, A. W. Gross, Tetrahedron Lett. 1984, 25, 495–498.

[42] P. A. Bartlett, K. K. Jernstedt, Tetrahedron Lett. 1980, 21,

1607–1610.

[43] S. D. Rychnovsky, P. A. Bartlett, J. Am. Chem. Soc. 1981, 103,

3963.

[68]

[69]

[70]

[44] J. D. White, L. Quaranta, G. Wang, J. Org. Chem. 2007, 72,

1717–1728.

N. J. Whitcombe, K. K. Hii, S. E. Gibson, Tetrahedron 2001,

57, 7449–7476.

E. C. Taylor, B. Liu, J. Org. Chem. 2001, 66, 3726–3738.

For the preparation of this compound see the Supporting In-

formation.

[45] J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 18, 734–

736.

[71]

[72]

[46] Y. Guindon, A. Slassi, J. Rancourt, G. Bantle, M. Ben-

cheqroun, L. Murtagh, E. Ghiro, G. Jung, J. Org. Chem. 1995,

60, 288–289.

[47] B. Guerin, C. Chabot, N. Mackintosh, W. W. Ogilvie, Y. Guin-

don, Can. J. Chem. 2000, 78, 852–867.

Received: December 29, 2009

Published Online: July 7, 2010

Eur. J. Org. Chem. 2010, 4642–4661

www.eurjoc.org

4661

Article Doi

Thione esters as substrates for the stereoselective alkylation of model compounds of nonactic acids

DOI: 10.1002/ejoc.200901513

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.200901513

Full text of DOI:10.1002/ejoc.200901513

Products guided by the article

R&D Labs maybe for 1250330-09-6

Relevant to this article

Hot Product