Hemisynthesis of methyl pyrethroates from γ-alkoxy-alkylidene malonates and isopropylidenediphenylsulfurane and isopropylidenetriphenylphosphorane

Tetrahedron 60 (2004) 7637–7658

Hemisynthesis of methyl pyrethroates from g-alkoxy-alkylidene

malonates and isopropylidenediphenylsulfurane and

isopropylidenetriphenylphosphorane

a,b

Alain Krief^aand Alexandre Froidbise

,

*

a

` ´ ´

Laboratoire de Chimie Organique de Synthese, Departement de Chimie, Facultes Universitaires N.D de la Paix, 61 rue de Bruxelles,

5000 Namur, Belgium

Fonds pour la Formation a la Recherche dans l’Industrie et l’Agriculture, 5 rue d’Egmont, 1000 Bruxelles, Belgium

b

`

Received 13 April 2004; revised 31 May 2004; accepted 1 June 2004

Available online 17 July 2004

Dedicated to Professor Dieter Seebach at the occasion of the 2003 Tetrahedron Prize with admiration for his extremely important contribution to

Organic Chemistry

Abstract—Hemisynthesis of methyl pyrethroates from g-alkoxy-alkylidene malonates and isopropylidenediphenylsulfurane and

isopropylidenetriphenylphosphorane is disclosed. It takes advantage of the high degree of stereocontrol observed in the cyclopropanation

of g-alkoxy-alkylidene malonates by the above mentioned ylides.

1. Introduction

duces, after some functional group manipulation, the

enantio-enriched methyl (d)-trans-chrysanthemate with a

74% ee (Scheme 2, entry b). In such transformation ethyl

3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylate has played the

role of chiral masked methyl 4-oxobutenoate.

We have been interested over the last ﬁfteen years to

develop new synthetic routes to chrysanthemic 1 and

deltamethrinic acid and related esters 2 (Scheme 1).¹

We have subsequently found that the cyclopropanation

reaction takes place from either the Re or the Si-face of the

electrophilic oleﬁn depending not only on the stereo-

chemistry at its allylic carbon bearing the alkoxy group

and of its [C,C] double bond but also on the nature of the

heteroatomic moiety present on the a-heterosubstituted

organometallic (Scheme 3).^5,7

Scheme 1. Structure of chrysanthemic and deltamethrinic compounds.

Important features of the reactions involving methyl 3-(2,2-

dimethyl-[1,3]dioxolan-4-yl)-acrylate, are collected in

Scheme 3.

One of our strategy involves the use of chiral g-alkoxy-a,b-

unsaturated esters as starting materials and isopropylidene-

diphenylsulfurane or isopropylidenetriphenylphosphorane

as cyclopropanating agents.^1e,2–6This interest arose from

our original work which involves the synthesis of methyl

(d,l)-trans-chrysanthemate in a single step from methyl

4-oxobutenoate and isopropylidenetriphenylphosphorane

(Scheme 2, entry a)^2aand from the work of Mulzer⁷who

described the diastereoselective cyclopropanation of ethyl

3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylate which pro-

Isopropylidenetriphenylphosphorane adds from the Si-face

of the E-stereoisomer (Scheme 3, entry a) whereas it adds

from the Re-face of its Z-stereoisomer (Scheme 3, entry c)

providing in both cases stereoselectively the trans-cyclo-

propane derivatives.^5a,b,7

Its sulfur ylide analogue however reacts by the Re-face of

methyl 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylate, irre-

spective of its stereochemistry. Furthermore the reaction

proved to be completely stereospeciﬁc since it leads to the

trans-cyclopropane carboxylate from the E-diastereoisomer

of methyl 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylate

Keywords: Asymmetric induction; Insecticide; g-Alkoxy enoates;

Deltamethrinic acid; Chrysanthemic acid.

*

Corresponding author. Tel.: 32-81-724539; fax: þ32-81-724536;

e-mail address: alainkrief@fund.ac.be

doi:10.1016/j.tet.2004.06.035

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A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

Scheme 2. Previous syntheses of trans-chrysanthemates.

Scheme 3. Stereocontrolled addition of P- and S-ylides to g-alkoxy enoates.

(Scheme 3; entry b) and to the cis-cyclopropane carboxylate

from its Z-diastereoisomer (Scheme 3; entry d).^5b–f

transformation of the acetal moiety to methyl hemi-

caronates.⁷

Asymmetric induction is as expected dependant on the

stereochemistry of the allylic carbon to which the alkoxy

group is attached. Enoates whose structures are described

above belong to the (S)-series. Their syntheses have been

selectively achieved using well established protocols

from the acetonides of ^D-glyceraldehyde derived from

(d)-mannitol.^1e,5a–d

The synthesis of methyl trans-chrysanthemate implies

isopropylidenetriphenylphosphorane (Ph₃PvCMe₂, THF,

20 8C, Scheme 2, entry b)^5c,7whereas that of methyl

deltamethrinate requires instead the use of dibromo-

methylenetriphenylphosphorane (CBr₄, PPh₃, THF, 20 8C,

cis: 81% yield, Scheme 4).^5b,c

The most important substrates are those which possess the

appropriate stereochemistry to produce, without any

stereochemical modiﬁcation, either methyl (1R)-trans-

chrysanthemate 2a or methyl (1R)-cis-deltamethrinate 2b.

Thus starting from the (S)-3-(2,2-dimethyl-[1,3]dioxolan-4-

yl)-acrylate derived from ^D-glyceraldehyde, the E-a,b-

unsaturated carboxylates and isopropylidenetriphenyl-

The strategy used to produce the required vinylcyclo-

propane carboxylates from the above mentioned adducts

involves (i) acid hydrolysis of the acetal moieties,

(ii) sodium periodate cleavage of the resulting diol and

(iii) Wittig oleﬁnation reaction. An even shorter approach

involves periodic acid which performs, in the same pot, the

Scheme 4. Synthesis of methyl deltamethrinate.

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

7639

phosphorane must be used for the synthesis of the former

compound (Scheme 2, entry b; Scheme 3, entry a)^2k,3and

Z-a,b-unsaturated carboxylates and isopropylidene-

diphenylsulfurane for the latter (Scheme 3, entry d;

Scheme 4).^5a,b

to the Hopkins¹⁰variation of the Corey–Winter reaction

((CH₂NMe)₂P–Ph, neat, 40 8C, 6 h, 89%; Scheme 5, entry

a)^5gwhereas the epoxy^5hsubstructure present on the latter

adduct has been transformed to the corresponding tri-

substituted C,C double bond on reaction with P₂I₄(CS₂,

pyridine, 5 h, reﬂux, 72%; Scheme 5, entry b).¹¹

The synthesis of methyl (1R)-cis-deltamethrinate works

ﬁne.^2i,kNot only the cis-content (100%) and the enantio-

meric excess (98%) are excellent, but also the strategy

which requires the introduction of the dibromomethylene

moiety at the end of the synthesis is reasonably good. This is

not the case of methyl (1R)-trans-chrysanthemate which

suffers both from quite poor enantiomeric excess (74–72%)

and quite lengthy functional group manipulation to produce

the vinyl side chain.^5,7

In the examples reported above the control of the

stereochemistry (1R)/(1S), cis/trans on the cyclopropane

ring depends on (i) the nature of the ylide (S or P) and (ii)

the stereochemistry (R or S) at [C-3] and also the

stereochemistry (Z or E) of the [C,C] double bond of

the g-alkoxy-a,b-unsaturated carboxylates.⁵Therefore the

stereochemistry of the [C,C] double bond has to be perfectly

controlled for successful enantioselective synthesis of

pyrethroic acids.

We have therefore designed two new routes to methyl (1R)-

trans-chrysanthemate which use both isopropylidene-

diphenylsulfurane as cyclopropanating agent (Scheme 5).^2t,u

The latter is known to provide much better asymmetric

induction than the related phosphorus ylide (Scheme 3).

This choice requires using as partner E-a,b-unsaturated

carboxylates possessing the inverted (R)-stereochemistry on

the chiral carbon bearing the alkoxy moiety.

Use of g-alkoxy-alkylidene malonates in place of the

corresponding a,b-unsaturated carboxylates should avoid

the latter constraint for the control of the face of attack and

therefore for the control of the stereochemistry at [C-2] on

the methyl chrysanthemate.⁶This strategy nevertheless

introduces other constraints since the stereochemistry at

[C-1] on the cyclopropane carboxylate is no longer related

to the stereochemistry of the [C,C] double bond of the

starting material and will be created at the time the tandem

decarboxylative-dealkylation is achieved. We expected that

the production of the trans-stereochemistry will take

advantage of steric hindrance between the group at [C-2]

and the carboxy group at [C-1] (Scheme 6, entry a)

whereas the cis-stereochemistry will derive from lactone

ring formation (Scheme 6, entry b).

In order to increase the diastereoselection and to shorten

the number of steps leading to methyl (1R)-trans-

chrysanthemate, we have performed the cyclopropanation

on methyl g-alkoxy-a,b-unsaturated carboxylates whose

hydrocarbon content provides, after sequential cyclopropa-

nation (Me₂CvSPh₂–LiBF₄, DME, 278 8C, 2 h, 278 to

20 8C, 1 h) and reductive decomposition, directly the

desired compound. Methyl (R)-3-(5,5-dimethyl-2-thioxo-

[1,3]dioxolan-4-yl)-^5gand (R)-3-(3,3-dimethyl-oxiranyl)-^5h

acrylates (Scheme 5, entries a and b, respectively) proved to

be the perfect candidates: (i) they are readily prepared from

methyl 5-methyl-hexa-2,4-dienoate and AD-mix b using

Sharpless catalytic asymmetric dihydroxylation reaction

(AD reaction, Scheme 5, entry a)^8aand 3-methyl-but-2-en-

1-ol, titanium tetraisopropoxide, tert-butylhydroperoxide

and l-diisopropyl tartrate according to Sharpless catalytic

asymmetric epoxidation of allyl alcohols (AE reaction,

Scheme 5, entry b)⁹respectively, (ii) after cyclopropanation

has been achieved the thionocarbonate substructure present

on the former product can be efﬁciently reduced according

In order to achieve the two approaches leading to each of the

two epimeric cyclopropane moieties at [C-2] present in

chrysanthemates 2a and deltamethrinates 2b, we had to ﬁnd

cyclopropanating agents able to react with complete

stereocontrol but divergently on the same methyl

g-alkoxy-alkylidene malonate (Scheme 6).⁶

Another less constraining approach uses the same reagent

but requires the synthesis of each of the two enantiomers of

methyl g-alkoxy-alkylidene malonate such as 2-(2,2-

dimethyl-[1,3]dioxolan-4-ylmethylene)-malonic acid

dimethyl ester (Scheme 7).

Scheme 5. Straightforward synthesis of methyl (1R)-trans-chrysanthemate.

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A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

Scheme 6. Planned enantioselective syntheses of pyrethroates using different ylides.

Scheme 7. Planned enantioselective syntheses of pyrethroates pyrethroates using different enoates.

We have successfully performed each of the two

approaches⁶but will present only the latter in this paper.^6a

ingredients are mixed at low temperature (dimethyl

malonate, TiCl₄, pyridine, THF, 278 to 20 8C, 72 h, 70%

yield on 10 g scale; 20 8C, 72 h, 24–41% yield).^6a

It was later found that even better results could be obtained

if both the oxidative cleavage of central diol of the terminal

diacetonide of ^D-mannitol (Pb(OAc)₄, THF, 0 8C, 0.2 h) and

the Knoevenagel reaction (dimethyl malonate, acetic

anhydride, reﬂux, 24 h, 85% yield, [a]²_D⁰¼þ20.1, c¼1.05;

ee .96%, Scheme 8, entry a) were carried out in the same

pot according to the procedure described for the corre-

sponding methyl malononitrile¹⁶(Scheme 8, entry d).

2. Synthesis of 2-(2,2-dimethyl-[1,3]dioxolan-4-

ylmethylene)-malonic acid esters, related malononitriles

and malonodinitrile

When we started this work 2-(2,2-dimethyl-[1,3]dioxolan-

4-ylmethylene)-malonic acid diethyl ester was already

known. It was produced in modest yield (24–30%), via a

Knoevenagel reaction¹²from (R)-2,2-dimethyl-[1,3]dioxo-

lane-4-carbaldehyde (the acetonide of ^D-glyceraldehyde)¹³

and diethyl malonate using piperidine as the catalyst

(toluene, 20 8C, 1–24 h)¹⁴but its stereochemical integrity

was not described. Piperidinium acetate which was

successfully used by Tietze¹²for related cases does not

lead to the desired compound using dimethyl malonate.

Titanium tetrachloride in the presence of pyridine¹⁵proved

the most suitable combination at the condition that the

The same process was successfully used for the synthesis of

methyl tertiobutyl and di-tertiobutyl-alkylidene malonates

((i) Pb(OAc)₄, THF, 0 8C, 0.2 h, (ii) malonate, acetic

anhydride, reﬂux, 24 h, 96 and 87% yield, respectively,

Scheme 8, entries b and c). Those conditions do not work

with malonodinitrile. The corresponding alkylidene

malonodinitrile has been however prepared in almost

Scheme 8. Synthesis of alkylidene malonates and alkylidene malononitriles derived from (R)-2,2-dimethyl-[1,3]dioxolane-4-carbaldehyde.

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

7641

quantitative yield, on reaction of the acetonide of

D-glyceraldehyde and malonodinitrile in the presence of

4-N,N-dimethylaminopyridine (CH₂Cl₂, 0 8C, 1 h, 20 8C,

quantitative yield) but its isolation from 4-N,N-dimethyl-

aminopyridine was unsuccessful and it has been used

without puriﬁcation in the next step.

(1.2 equiv. (COCl)₂, 2.5 equiv. DMSO, 5 equiv. NEt₃,

260 8C, 37%),^18ausing the procedure we already disclosed

(TiCl₄, pyridine, THF, 278 to 20 8C, 72 h, 45% yield,

Scheme 9).^6aThe latter reaction does not work if PCC is

used instead of Swern oxidation.^18b,c

We have checked the stereochemical purity of 2-(2,2-

dimethyl-[1,3]dioxolan-4-ylmethylene)-malonic acid

dimethyl ester just prepared by comparison on HPLC

(Diacel, Chiracel, ODH, isopropanol/hexane: 3/7 (v/v)

1 ml/min; 47 bar; l_DET254 nm) of an authentic racemic

sample prepared on reaction of acetonide of rac-glycer-

aldehyde, obtained from glycerol on acetalization (acetone,

APTS, pentane, 60 8C, 41 h, 98%)¹⁷and Swern oxidation

3. Synthesis of 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-

dimethyl-cyclopropane-1,1-dicarboxylic acid dialkyl

esters, related ester, nitriles and dinitriles

Isopropylidenetriphenylphosphorane generated from the

corresponding isopropyltriphenylphosphonium iodide and

n-butyllithium (THF, 0 8C, 0.2 h)¹⁹and isopropylidene-

diphenylsulfurane synthesized from isopropyldiphenyl-

sulfonium tetraﬂuoroborate, LDA and dichloromethane

(DME, 278 8C, 0.5 h)²⁰have been successfully

reacted with 2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl-

ene)-malonic acid dimethyl ester and provide both 3-(2,2-

dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-

1,1-dicarboxylic acid dimethyl ester in extremely good

yield and enantioselectivity (Scheme 10).^6aThe two ylides

react by the same Re-face of the alkylidene malonate as it

has been described from the reaction of these two ylides

with 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylic acid

methyl ester.

Scheme 9. Synthesis of rac-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethylene)-

malonic acid dimethyl ester.

Scheme 10. Cyclopropanation of-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethylene)-malonic acid dimethyl ester.

Scheme 11. Cyclopropanation of alkylidenemalonates.

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A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

Scheme 12. Cyclopropanation of alkylidene malononitriles.

Scheme 13. Structure determination of 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-1,1-dicarboxylic acid dimethyl ester.

Isopropylidenediphenylsulfurane (DME, 278 8C, 2 h,

20 8C, 1 h, 76% yield, de 98%, Scheme 10, entry a) proved

be more reactive than its phosphorus analogue (THF, 0 8C,

24 h, 80%, de 98%, Scheme 10, entry d, compare to entries

b and c).^6a

enantiomeric integrity has not been ascertained, just after its

synthesis due to its instability.

The structure of all the cyclopropane derivatives has been

ascertained by physical methods and in the case of

cyclopropane dicarboxylates has been in complement

achieved by comparison with authentic samples (Scheme

13). Thus 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-

dimethyl-cyclopropane-1,1-dicarboxylic acid dimethyl

ester resulting from the reaction of 2-(2,2-dimethyl-

[1,3]dioxolan-4-ylmethylene)-malonic acid dimethyl ester

with isopropylidenediphenylsulfurane (Scheme 13) has

been compared to an authentic sample prepared in a

multistep sequence from methyl 3-(2,2-dimethyl-[1,3]-

dioxolan-4-yl)-acrylate and isopropylidenetriphenylphos-

phorane followed by a tandem metalation–carboxylation

Similar results were obtained when instead the reactions are

carried out on the related di-tertiobutyl malonate

(Scheme 11, entries a–c) or on a 45/55 Z/E diastereomerize

mixture of tertiobutyl methyl malonates (Scheme 11, entry

a) in this case the reaction proceeds with complete

facial control but leads to about a 45/55 mixture of

cis/trans cyclopropane derivatives (Scheme 11, entries

d–g).

The reaction still proceeds with complete control of the

relative stereochemistry on the cyclopropane ring when

instead performed on the related alkylidene malononitrile

possessing the E-stereochemistry since the cyclopropane

derivatives belong both to the trans-series. Reaction by the

Re face is now predominant but no longer exclusive (de 60;

Scheme 12, entries a and b) whatever the nature of the ylide

is. And interestingly, almost no stereocontrol is found with

alkylidene malonodinitrile (de 4–18%; (Scheme 12, entries

c and d). In such case the reaction has been carried out on

the crude mixture of the electrophilic derivative whose

Figure 1. Structure of methyl 1-cyano-3-(2,2-dimethyl-[1,3]dioxolan-4-

yl)-2,2-dimethyl-cyclopropanecarboxylate.

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

7643

Scheme 14. Strategies for deltamethrinic acid synthesis.

reaction of the resulting methyl 3-(2,2-dimethyl-[1,3]dioxo-

lan-4-yl)-2,2-dimethyl-cyclopropanecarboxate ((i) LDA,

THF, 278 8C, 0.75 h, (ii) ClCO₂Me, THF, 278 to 20 8C,

Scheme 13).

for that purpose requires the lactone ring formation. The

most suitable approach would have been ideally to generate

at ﬁrst the lactone ring then to perform the demethylation–

decarboxylation reaction (Scheme 14, entry a). This should

avoid the extra trans/cis-epimerisation which should be

otherwise required (Scheme 14, entry b).

Furthermore, 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-

dimethyl-cyclopropane-1,1-dicarboxylic acid dimethyl

ester as well as the stereoisomeric mixture of 3-(2,2-

dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-

1,carboxylic acid methyl ester-1-carboxylic acid tertiobutyl

ester have been both transformed to the 3-(2,2-dimethyl-

[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-1,1-dicar-

boxylic acid ditertiobutyl ester (Scheme 13) on reaction

with potassium t-butoxide in THF, 278 to 20 8C, 2 h, 92 and

95% yield, respectively).

In fact the decarboxylation reaction of dimethyl cyclo-

propane dicarboxylates is not as easy as that of dimethyl

malonates missing the cyclopropane ring probably because

the enol or enolate intermediate has a lower propensity to be

formed due to the extra strain induced by the three-

membered ring (Scheme 14, entry b). This effect is at its

paroxysm when decarboxylation is carried out on

4-hydroxymethyl-6,6-dimethyl-3-oxa-bicyclo[3.1.0]hexan-

2-one because the enol or enolate intermediate is at a

bridgehead position (Scheme 14, entry a).

Finally, the structure of the major stereoisomer of methyl

1-cyano-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-

cyclopropanecarboxylate has been unambiguously accessed

by X-ray crystallography (Fig. 1).^6c

We tried the ﬁrst route because it was the most challenging

one. We planned to perform the decarboxylation reaction

through a Barton reaction²¹involving a radical process as it

was described in a related series.^22a

4. Synthesis of deltamethrinic acid from 3(S)-(2,2-

dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-

cyclopropane-1,1-dicarboxylic acid dimethyl ester

Acid catalyzed dioxolane ring opening was successfully

achieved using aqueous hydrochloric acid (Scheme 16).

Careful monitoring of this reaction shows however that

The (3R) stereochemistry at [C-3] of 3(R)-(2,2-dimethyl-

[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-1,1-dicar-

boxylic acid dimethyl ester suggests that it could be a

valuable precursor of deltamethrinic acid. The strategy used

methyl

3-(1,2-dihydroxy-ethyl)-2,2-dimethyl-cyclo-

propane-1,1-dicarboxylate is efﬁciently obtained if the

reaction is performed within a few hours (10% aq. HCl,

20 8C, 1.5 h, 76% yield, Scheme 15, entry a). Otherwise,

Scheme 15. Unsuccessful decarboxylation reaction.

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A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

Scheme 16. Radical promoted decarboxylation reaction.

cyclization of the diol on the cis-carbomethoxy group takes

place and leads to methyl 4-hydroxymethyl-6,6-dimethyl-2-

oxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxylate in very good

yield (10% aq. HCl, 20 8C, 50 h, 89% yield, Scheme 16,

entry b). Protection as tert-butyl dimethylsilylether of the

hydroxyl group of the resulting lactone has been achieved

on reaction with tert-butyl dimethylsilylchloride (TBSCl,

imidazole, DMF, 20 8C, 1 h, 92%, Scheme 15, entry b). We

however gave up this approach because the milder

conditions used which involves magnesium diiodide,²²as

reported above, induces the cyclopropane ring opening rather

than the desired dimethylation–carboxylation reaction (MgI₂,

110 8C, 10 h, 54% or 80 8C, 13 h, 55%, Scheme 15).

carboxylic acid methyl ester (Scheme 16, entry b) instead of

the expected methyl cyclopropanecarboxylate (Scheme 16,

entry a).²²

We therefore turned our attention to the second approach in

which the decarboxylation of 3-(2,2-dimethyl-[1,3]dioxo-

lan-4-ylmethyl)-2,2-dimethyl-cyclopropane-1,1-dicar-

boxylic acid dimethyl ester has to be achieved ﬁrst but this

was not a simple task.

We decided not to use acidic conditions to avoid competing

deacetalisation which would favor lactone ring formation

and tried to use almost neutral conditions which are known

for allowing a tandem dealkylation–decarboxylation by

substitution at the methyl of the methoxy group of 3-(2,2-

dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-

1,1-dicarboxylic acid dimethyl ester.

We have also unsuccessfully tried to perform the

decarboxylation of 2,2-dimethyl-cyclopropane-1,1-

dicarboxylic acid methyl ester as model using the Barton²¹

procedure since the end-product proved to be mainly 2,2-

dimethyl-1-(pyridin-2-ylsulfanylcarbonyl)-cyclopropane-

The most usual conditions which use metal halides or

Scheme 17. Decarboxylation of alkylidene malonates.

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

7645

Scheme 18. Acid catalyzed ring opening of dioxolane moiety. Potential lactone ring formation.

sodium cyanide in DMF or DMSO required too drastic

conditions (160–140 8C, 6–60 h, Scheme 17, entries a and

b).^4a,23They in fact leads to the formation of substantial

amount of methyl 3-(2,2-dimethyl-[1,3]dioxolan-4-

ylmethyl)-4-methyl-pent-4-enoate resulting from cyclo-

propane ring opening. Other conditions which used instead

metal chalcogenides in DMF²⁴proceed at lower tempera-

ture but require too longer time to go to completion and

methyl 3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2,2-

dimethyl-cyclopropanecarboxylate is obtained in quite

modest yields (90 8C, 26–30 h, 54–68%, Scheme 17,

entry c). Tetramethyl ammonium acetate in anhydrous

polar solvents, which was used by Trost,²⁵proved to be the

best compromise since the desired compound, methyl

3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclo-

propanecarboxylate is obtained, in extremely high yield, as

a mixture of diastereoisomers, under relatively mild

conditions and without competing cyclopropane ring open-

ing (Scheme 17, entry d).

trans-3-(2,3-dihydroxy-propyl)-2,2-dimethyl-cyclo-

propanecarboxylate and 4-hydroxymethyl-6,6-dimethyl-3-

oxa-bicyclo[3.1.0]hexan-2-one resulting from lactonization

of the cis-diastereoisomer (10% aq. HCl, MeOH, 20 8C,

0.5 h, [a]²_D⁰¼268.7 (CHCl₃, c¼1.27), Scheme 18).

It was also found that lactonization of methyl cis-3-(2,3-

dihydroxy-propyl)-2,2-dimethyl-cyclopropanecarboxylate,

occurs even faster than that of 3-(2,3-dihydroxy-propyl)-

2,2-dimethyl-cyclopropane-1,1-dicarboxylic acid dimethyl

ester (compare Scheme 15 to Scheme 18, entry a).

Lactonization of the remaining methyl trans-3-(1,2-

dihydroxy-ethyl)-2,2-dimethyl-cyclopropanecarboxylate to

4-hydroxymethyl-6,6-dimethyl-3-oxa-bicyclo[3.1.0]hexan-

2-one, which is required to reach the cis-cyclopropane

derivative, was problematic. No reaction takes place under

conditions which successfully allow lactonization of methyl

3-hydroxymethyl-2,2-dimethyl-cyclopropanecarboxylate^2f

(i) 1 or 2 equiv. t-BuOK, benzene, 80 8C, 6 h; (ii) 10% aq.

HCl, Scheme 19) and other conditions which use lithium

hydride to protect each of the two hydroxyl groups as their

lithium alcoholates and potassium t-butoxide to perform the

epimerization reaction fail too.

Acid hydrolysis of the 70/30 trans/cis-mixture of dia-

stereoisomeric methyl 3-(2,2-dimethyl-[1,3]dioxolan-4-

ylmethyl)-2,2-dimethyl-cyclopropanecarboxylate

(Scheme 17, entry d) leads to a 70/30 mixture of methyl

Successful contrathermodynamic trans/cis-isomerisation

has been ﬁnally achieved on reaction of methyl 3-(1-

hydroxy-2-trityloxy-ethyl)-2,2-dimethyl-cyclopropane-

carboxylate, which possesses a trityloxy group at its

terminus, with potassium t-butoxide in benzene

(Scheme 20).

The trityl protecting group which was selectively introduced

on reaction of methyl trans-3-(1,2-dihydroxy-ethyl)-2,2-

dimethyl-cyclopropanecarboxylate with N,N-4-dimethyl-

amino-N-triphenylmethylpyridinium chloride (prepared

Scheme 19. Lactones synthesis by cyclization of g-hydroxy esters.

Scheme 20. The lactone ring formation requires the protection of the primary hydroxyl group present on the diol, as a trityl ether.

7646

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

Scheme 21. AD-mix is able to oxidize 2,5-dimethyl-hexadiene but not 2-(3-methyl-but-2-enylidene)-malonic acid dimethyl ester.

from dimethylaminopyridine and triphenylmethyl-

chloride)²⁶was then easily removed from 6,6-dimethyl-4-

trityloxymethyl-3-oxa-bicyclo[3.1.0]hexan-2-one on acid

hydrolysis (10% aq. HCl, MeOH, 20 8C, 1 h,

Scheme 20).²⁷The synthesis of deltamethrinic acid from

this compound has been already disclosed.²⁸

(CH₂(CO₂Me)₂, TiCl₄, pyridine, THF, 278 to 20 8C, 72 h,

85%, Scheme 23).

A much straightforward approach to 2-(2,2,5,5-tetramethyl-

[1,3]dioxolan-4-ylmethylene)-malonic acid dimethyl ester

which instead would have implied 2-(3-methyl-but-2-

enylidene)-malonic acid dimethyl ester and AD-mix b

proved to be unsuccessful (20 8C, 140 h, 0% yield,

Scheme 21).

5. Synthesis of methyl trans-chrysanthemate from 3(R)-

(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-

cyclopropane-1,1-dicarboxylic acid dimethyl ester

Cyclopropanation of 2-(2,2,5,5-tetramethyl-[1,3]dioxolan-

4-ylmethylene)-malonic acid dimethyl ester using iso-

propylidenetriphenylphosphorane or isopropylidene-

diphenylsulfurane proved to be excellent (Me₂CvPPh₃,

LiI, 0 8C, 1 h then 20 8C, 24 h; 82% yield, de 90%,

Scheme 22, entry a; Me₂CvSPh₂, BF₄, 278 8C, 2 h,

20 8C, 1 h, 76%, de 98%, Scheme 22, entry b).

The synthesis of methyl trans-chrysanthemate has been

performed, as outlined in Schemes 23 and 24 from 2,5-

dimethyl-hexadiene using Sharpless AD reaction^8a(AD-

mix b, K₂OsO₂(OH)₄, DHQD, K₃Fe(CN)₆, K₂CO₃,

t-BuOH–H₂O (1:1), MeSO₂NH₂, 20 8C, 2 h, 89% yield).

Protection of the resulting diol (Me₂C(OMe)₂, acetone,

pTSA, 99% yield) leads to 2,2,4,4-tetramethyl-5-(2-methyl-

propenyl)-[1,3]dioxolane. Its ozonolysis followed by

reduction of the resulting ozonide ((i) O₃, CH₂Cl₂,

278 8C, 2 h (ii) DMS, 20 8C, 12 h) leads to 2,2,5,5-

tetramethyl-[1,3]dioxolane-4-carbaldehyde which has been

subjected without puriﬁcation to the Knoevenagel reaction

We have been unable to produce alkyl trans-chrysanthe-

mates from 2,2-dimethyl-3-(2,2,5,5-tetramethyl-[1,3]dioxo-

lan-4-yl)-cyclopropane-1,1-dicarboxylic acid dimethyl

ester by the route disclosed in Scheme 23, entry a which

involves acetonide deprotection and thionocarbonate

reduction. We have been unable to isolate the expected

Scheme 22. Cyclopropanation of 2-(2,2,5,5-tetramethyl-[1,3]dioxolan-4-ylmethylene)-malonic acid dimethyl ester.

Scheme 23. Unsuccessful deoxygenation of a diol moiety.

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

7647

3-(1,2-dihydroxy-2-methyl-propyl)-2,2-dimethyl-cyclopro-

pane-1,1-dicarboxylic acid dimethyl ester due to the

extreme ease with which it cyclizes to 4-(1-hydroxy-1-

methyl-ethyl)-6,6-dimethyl-2-oxo-3-oxa-bicyclo[3.1.0]-

hexane-1-carboxylic acid methyl ester (Scheme 23, entry b).

concerted cycloadditions and performed under different

conditions, for example, in different solvents.^5c,7,29–48

Although several explanations and calculations,^36,46b,c,49

often based on the Felkin–Anh model^50–55have been

disclosed, till now there is no model which explain all these

results and it is therefore impossible to predict, unless very

closely related examples are available, the stereochemical

course of addition reaction to E-g-alkoxy-a,b-unsaturated

esters, their Z-stereoisomers and related g-alkoxy-alkyl-

idene malonates. We are working towards this end.

It is interesting to compare the ease of that lactone ring

formation (Scheme 25, entry b) to that of the related

desdimethylated analogue disclosed in Scheme 15 or the

cis-cyclopropanecarboxylate disclosed in Scheme 19, entry

a) which all possess the same relative diastereoisomeric

relationship around the stereogenic centers.

7. Experimental

7.1. General

In order to achieve the desired transformation leading to

(1R)-trans-chrysanthemic we used a more lengthy route

which requires to perform at ﬁrst the decarboxylation of 2,2-

dimethyl-3-(2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-cyclo-

propane-1,1-dicarboxylic acid dimethyl ester and to effect

the deoxygenation of the side chain at the end of the

sequence (Scheme 24). Almost all the reactions which have

been used for such purpose have already used but in another

order for the synthesis of deltamethrin acid disclosed above.

NMR spectra were recorded on a JEOL JNM EX-400 (400

and 100.6 MHz, for ¹H and ¹³C, respectively) or JEOL JNM

EX-90 (90 and 22.5 MHz, for ¹H and ¹³C, respectively). All

spectra were carried out in CDCl₃unless otherwise stated

using TMS as internal standard. IR spectra reported in cm²¹

were recorded on a BIO-RAD FTS-165 spectrometer.

Melting points were recorded on a Tottoli–Bu¨chi apparatus

and are uncorrected. Optical rotations were measured on a

Helwett–Packard digital polarimeter, the concentration

being expressed as c: g/100 ml. Mass spectra were recorded

on a HP 5989B spectrometer. Elemental analyses were

6. Conclusion

Addition of various reagents to alicyclic electrophilic

oleﬁns bearing an alkoxy group in g-position has been the

subject of intensive work over the last twenty years.²⁹Most

of these reactions involve g-alkoxy-a,b-unsaturated esters

whose C,C double bond is either E or Z and g-alkoxy-

malonates possessing a stereogenic centre at C-g. Those can

be attacked either by one or the other face producing

compounds possessing the syn- or anti-stereochemistry

between Cb and C-g (Scheme 25).

´

performed by the Service d’Analyse de l’Universite Pierre

et Marie Curie, 75252 Paris Cedex 05, France. X-ray

diffraction measurements were carried out at the

´

‘Laboratoire de Chimie Moleculaire Structurale des

FUNDP-Namur-Belgium’. lGC²l were recorded on a HP

5890A chromatograph using a capillary SE30 column

(25 m£0.25 mm£0.2 mm) in the following standard con-

ditions: T detector: 250 8C, T injector: 250 8C, He pressure

(1 ml/min). The oven temperatures were, respectively:

program A (heating from 100 to 220 8C with a temperature

increase of 10 8C/min), program B (heating from 60 to

220 8C with a temperature increase of 10 8C/min). Enantio-

These belong to different class of ‘reagents’ and are

involved in a large variety of organic reaction implying

polar or radical type of additions, concerted and non

Scheme 24. Synthesis of 2,2-dimethyl-3-(2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-cyclopropane-1,1-dicarboxylic acid dimethyl ester.

Scheme 25. syn- or anti-adducts produced on addition of various reagents to g-alkoxy-a,b-unsaturated esters.

7648

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

meric excess (e.e.) were determined by lGC²l using a chiral

capillary b-cyclodextrine column (Diacel, Chiracel, ODH,

25 m£0.25 mm£0.2 mm) in the following standard con-

ditions: T detector: 250 8C, T injector: 250 8C, He pressure

(1 ml/min).TLC was performed on pre-made commercial

glass-backed plate SiO₂(Merck 5719, 250 mesh) 60PF₂₅₄as

ﬂuorescent indicator. Compounds were visualized by UV

illumination (254 nm) and by heating to 150 8C after

spraying 20% phosphomolybdic acid in ethanol. Preparative

layer chromatography (PLC) was performed on SiO₂plates

from silica gel 60PF₂₅₄(Merck 5719) All reactions were

carried under Ar, unless stated otherwise. Solvents were

freshly distilled from Na/benzophenone (THF, Et₂O), Na

(toluene), LiAlH₄(DME), Calcium hydride (DMSO,

HMPA) or P₂O₅(CH₂Cl₂). Column chromatography was

performed using silica gel 60 under usual techniques. 1,2-

5,6-Diisopropylidene-^D-mannitol,⁵⁵2,3-O-isopropylidene-

D-glyceraldehyde,⁵⁵and 3,4-isopropylidene-D-mannitol^12c

were prepared following the procedures described in the

literature.

CDCl₃) 164.6, 163.6, 148.4, 128.1, 110.3, 73.1, 68.8, 52.4,

52.3, 26.1, 25.3; IR (ﬁlm, KBr) 2989, 2956, 2883, 1733,

1655, 1438, 1373, 1258, 1224, 1155, 1060, 1033, 986, 942,

840, 794, 765, 647 cm²¹; GC/MS m/z 244 (M^þ), 229, 214,

182, 169, 156, 138, 123, 85, 59. Anal. Calcd for C₁₁H₁₆O₆:

C, 54.09; H, 6.60. Found C, 53.96; H, 6.62.

7.1.2. Synthesis of (2,2-dimethyl-[1,3]dioxolan-4-yl)-

methanol. Glycerol (109 mmol, 10.0 g), acetone (ACS

reagent, 30 ml), pentane (30 ml) and p-toluenesulfonic acid

(1.57 mmol, 300 mg) were successively introduced into a

vessel ﬁtted with a Dean–Stark. The mixture was then

stirred at reﬂux for 41 h. After cooling, sodium acetate

(1.83 mmol, 150 mg) was added. The mixture was ﬁltered

and the solvents were evaporated under reduced pressure

to give the pure alcohol (14.1 g, 98%) as alight yellow

oil. lGC²l, program B, 2.5 min; ¹H NMR d (400 MHz,

CDCl₃) 4.28–3.57 (br, 3H, CH–OHþCH–O), 2.6 (br, 3H,

CH₂–OHþOH), 1.45 (s, 3H, CH₃), 1.39 (s, 3H, CH₃); IR

(ﬁlm, KBr) 3435, 2988, 2937, 1458, 1381, 1372, 1257,

1214, 1157, 1118, 1074, 1053, 971, 845, 793 cm²¹. Spectral

and analytical data are in agreement with the reported

data.^17a

7.1.1. Synthesis of 2-(2,2-dimethyl-[1,3]dioxolan-4-

ylmethylene)-malonic acid dimethyl ester. Procedure A.

Titanium (IV) chloride (140 mmol, 26.6 g) was added

dropwise under an atmosphere of argon, to 420 ml of

anhydrous THF maintained at 278 8C. The resulting yellow

suspension was kept at this temperature for 0.25 h. A

mixture of dimethyl malonate (200 mmol, 26.1 g), 2,3-O-

isopropylidene-^D-glyceraldehyde (70 mmol, 9.1 g) and

pyridine (280 mmol, 22.1 g) was then added dropwise to

the yellow suspension. The resulting mixture was stirred at

20 8C for 120 h before the reaction was quenched with a

saturated ammonium chloride solution (200 ml). The

aqueous phase was extracted with ether (7£100 ml). The

combined organic layers were washed with brine (100 ml),

dried (MgSO₄) and the solvents were removed under

reduced pressure to give 33.5 g of brown oil. The crude

product (33.3 g) was puriﬁed by distillation (bp 95 8C,

0.2 mm Hg) to yield the pure alkylidene malonate (12.0 g,

70%) as a yellow oil.

7.1.3. Synthesis of 2,3-O-isopropylidene-(d,l)-glyceralde-

hyde. Freshly distilled DMSO (48 mmol, 3.75 g), diluted in

5 ml of anhydrous dichloromethane, was added dropwise to

a well stirred solution of oxalyl chloride (22 mmol, 2.79 g)

in anhydrous dichloromethane (50 ml) maintained at

260 8C. The mixture became yellow and (2,2-dimethyl-

[1,3]dioxolan-4-yl)-methanol (20 mmol, 2.64 g), diluted

with 10 ml of anhydrous dichloromethane, was introduced

dropwise to the solution which was then stirred for 15 min.

Triethylamine (100 mmol, 10.1 g) was added dropwise and

the mixture was then heated to room temperature. Water

(50 ml) and dichloromethane (50 ml) were added. Organic

layer was washed with water (25 ml) and the combined

aqueous layers were extracted with dichloromethane

(3£50 ml). Organic layers were dried (MgSO₄) and the

solvents were evaporated under reduced pressure to give

1.60 g of crude material which was rapidly puriﬁed by

distillation (40 8C, 20 mm Hg) to yield the aldehyde

(893 mg, 37%) as colorless oil. lGC²l, program A,

1.6 min; ¹H NMR d (400 MHz, CDCl₃) 9.71 (d, 1H,

J¼2.2 Hz, CHvO), 4.61–3.91 (br, 3H, 3CH–OH), 1.49 (s,

3H, CH₃), 1.44 (s, 3H, CH₃); IR (ﬁlm, KBr) 3423, 2989,

2938, 2893, 1737, 1457, 1375, 1256, 1217, 1154, 1154,

1074, 848 cm²¹. Spectral data are in agreement with those

from the enantiopure 2,3-O-isopropylidene-(d)-glyceralde-

hyde.⁵⁵

Procedure B. Lead tetracetate (12.4 mmol, 5.5 g) was added

under an atmosphere of argon, in small portions to a solution

of 1,2-5,6-diisopropylidene-^D-mannitol (11.4 mmol, 3.0 g)

in anhydrous THF (200 ml) maintained at 0 8C. The mixture

was stirred at 0 8C for 10 min and dimethyl malonate

(30 mmol, 3.96 g) and freshly distilled acetic anhydride

(4.65 ml) were added. The resulting mixture was then

heated under reﬂux for 24 h. After cooling, the solution was

ﬁltered and the solvents eliminated under reduced pressure.

The residue was dissolved in dichloromethane (100 ml),

washed with a saturated aqueous sodium bicarbonate

solution (1£20 ml) and brine (1£20 ml) and dried

(MgSO₄). The solvents were removed under reduced

pressure to give an orange oil which was puriﬁed by

distillation (bp 95 8C, 0.2 mm Hg) to yield the pure

alkylidene malonate (4.73 g, 85%) as a yellow oil.

[a]²_D⁰¼þ20.4 (c 1.0, CHCl₃); TLC, SiO₂: R_f0.5 (pentane/

ether: 70/30). lGC²l, program A, 5.3 min; ¹H NMR d

(400 MHz, CDCl₃) 7.02 (d, 1H, J¼6.9 Hz, CHvC(CO₂-

Me)₂), 4.90 (m, 1H, CH–O), 4.27 (m, 1H, CH–O), 3.83 (s,

3H, OCH₃), 3.80 (s, 3H, OCH₃), 3.72 (m, 3H, CH–O), 1.44

(s, 3H, CH₃), 1.38 (s, 3H, CH₃). ¹³C NMR d (100.4 MHz,

7.1.4. Synthesis of (d,l) 2-(2,2-dimethyl-[1,3]dioxolan-4-

ylmethylene)-malonic acid dimethyl ester. Has been

achieved on 2,3-O-isopropylidene-(d,l)-glyceraldehyde

(10 mmol, 1.30 g) according to the procedure described

for 2,3-O-isopropylidene-^D-glyceraldehyde (see above).

7.1.5. Synthesis of 2-(2,2-dimethyl-[1,3]dioxolan-4-

ylmethylene) malonic di-tert-butyl ester. It has been

performed according to the Procedure B described above for

the related dimethyl ester using lead tetracetate (18.6 mmol,

8.4 g) and di-tert-butyl malonate (45 mmol, 9.6 g) to yield

pure alkylidene malonate (10.7 g, 96%) as a colorless oil.

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

7649

[a]²_D⁰¼þ15.8 (c 2.37, CHCl₃); TLC, SiO₂: R_f0.7 (pentane/

ether: 90/10). lGC²l, program A, 10.9 min; ¹H NMR d

(400 MHz, CDCl₃) 6.76 (d, 1H, J¼7.5 Hz, CHvC(CO₂-

tBu)₂), 4.88 (m, 1H, CH–O–), 4.26 (m, 1H, CH–O–), 3.72

(m, 1H, CH–O–), 1.53 (s, 9H, C(CH₃)₃), 1.51 (s, 9H,

C(CH₃)₃), 1.46 (s, 3H, CH₃), 1.40 (s, 3H, CH₃); ¹³C NMR d

(100.4 MHz, CDCl₃) 164.0, 162.8, 144.3, 139.0, 132.3,

110.2, 82.3, 82.0, 73.1, 72.3, 68.9, 27.7, 26.3, 25.5; IR (ﬁlm,

KBr) 2982, 2937, 2877, 1725, 1654, 1479, 1457, 1393,

ylmethylene)-malononitrile. Malononitrile (5.5 mmol,

360 mg) was added under an atmosphere of argon, to a

solution of 4-N,N-dimethylaminopyridine (0.5 mmol,

60 mg)

and

2,3-O-isopropylidene-^D-glyceraldehyde

(5 mmol, 655 mg) in anhydrous dichloromethane (10 ml)

maintained at 0 8C. The orange mixture was then stirred at

0 8C for 1 h and at 20 8C for 2 h. The solvents were then

evaporated under reduced pressure to give the crude

compound (1.11 g), as an orange glue which could not be

puriﬁed and was used directly in the next reactions. This

compound decomposes rapidly on alumina, silica gel and by

heating. ¹H NMR d (400 MHz, CDCl₃) 7.26 (d, 1H,

J¼7.6 Hz, CHvC(CN)₂), 5.34 (m, 1H, CH–O), 4.35 (m,

1H, CH–O), 3.86 (m, 1H, CH–O), 1.51 (s, 3H, CH₃), 1.43

(s, 3H, CH₃); IR (ﬁlm, KBr) 3348, 3332, 3055, 2992, 2941,

2899, 2241, 2202, 2169, 2112, 1757, 1720, 1650, 1617,

1570, 1481, 1457, 1379, 1345, 1264, 1217, 1153, 1122,

1371, 1273, 1251, 1162, 1063, 1024, 904, 851, 787 cm²¹

;

GC/MS m/z 328 (M^þ), 273, 217, 199, 187, 159, 138, 123,

85, 59. Anal. Calcd for C₁₇H₂₈O₆: C, 62.18; H, 8.59. Found

C, 62.15; H, 8.67.

7.1.6. Synthesis of 2-(2,2-dimethyl-[1,3]dioxolan-4-

ylmethylene)-malonic acid tert-butyl ester methyl ester.

It has been performed according to the Procedure B

described above for the related dimethyl ester using lead

tetracetate (18.6 mmol, 8.4 g) and tert-butyl-methyl

malonate (45 mmol, 7.8 g) to give an orange oil (16.3 g)

which was puriﬁed by column chromatography (pentane/

ether: 70/30 (v/v)) to yield pure alkylidene malonate (8.5 g,

87%) as a colorless oil (45/55 mixture of two isomers);

TLC, SiO₂: R_f0.63 (pentane/ether: 70/30). lGC²l, program

A, 9.2 min; ¹H NMR d (400 MHz, CDCl₃) 6.90 (d,

J¼7.1 Hz, CHvC(CO₂R)₂E), 6.88 (d, J¼7.0 Hz,

CHvC(CO₂R)₂Z), 4.91 (m, CH–O E), 4.87 (m, CH–O

Z), 4.26 (br, CH–O ZþE), 3.82 (s, OCH₃Z), 3.80 (s, OCH₃

E), 3.75–3.70 (br, CH–O ZþE), 1.53 (s, C(CH₃)₃E), 1.50

(s, C(CH₃)₃Z), 1.45 (s, CH₃ZþE), 1.40 (s, CH₃E), 1.39 (s,

CH₃Z); ¹³C NMR d (100.4 MHz, CDCl₃) 165.4, 164.7,

163.6, 162.5, 146.3, 140.4, 139.8, 130.5, 130.3, 110.5, 82.9,

82.5, 79.4, 76.4, 73.3, 73.2, 72.4, 69.0, 66.3, 52.4, 52.3,

27.9, 27.4, 26.7, 26.4, 25.8, 25.5; IR (ﬁlm, KBr) 2986, 2955,

2939, 2881, 1731, 1656, 1478, 1457, 1438, 1372, 1329,

1256, 1225, 1160, 1062, 1032, 967, 905, 847, 754,

645 cm²¹; GC/MS m/z 287 (M^þþ1), 244, 229, 215, 201,

177, 169, 143, 115, 101, 85, 72, 59. Anal. Calcd for

C₁₄H₂₂O₆: C, 58.72; 7.74. Found C, 58.65; H, 7.79.

1064, 966, 919, 840, 738 cm²¹

.

7.1.9. Synthesis of 2,4-dimethyl-hex-4-ene-2,3-(R)-diol.

AD-mix b (15 g) was added in small portions to a well

stirred mixture of water (50 ml) and tert-butanol (50 ml) at

20 8C. Methane sulfonamide (10 mmol, 950 mg) was added

and the mixture was stirred at 20 8C for 10 min. 2,5-

Dimethyl-2,4-hexadiene (10 mmol, 1.1 g) was added drop-

wise to the solution and the mixture was stirred vigorously

at 20 8C for 2 h. Sodium bisulﬁte (15 g) was added in small

portions and the resulting grey mixture was kept at room

temperature for 1 h, extracted with ethyl acetate (3£70 ml).

Organic layers were washed with brine (2£10 ml) and dried

(MgSO₄). The solvents were removed under reduced

pressure to give 2.3 g of crude material which was puriﬁed

by column chromatography (pentane/ether: 0/100 (v/v)) to

yield the pure 2,4-dimethyl-hex-4-ene-2,3-(R)-diol (1.17 g,

89%) as a colorless oil. [a]²_D⁰¼þ9.57 (c 0.94, CHCl₃); TLC,

SiO₂: R_f0.61 (pentane/ethyl acetate: 0/100). lGC²l, program

A, 3.2 min; chiral lGC²l (b-Dextrine column, 110 8C

1

isotherm) 13,2 min; H NMR d (400 MHz, CDCl₃) 5.22

(d, 1H, J¼9.2 Hz, CHvCMe₂), 4.16 (d, 1H, J¼9.3 Hz,

CH–O), 2.19 (br, 2H, 2OH), 1.79 (s, 3H, CH₃), 1.72 (s, 3H,

CH₃), 1.18 (s, 3H, CH₃), 1.16 (s, 3H, CH₃); ¹³C NMR d

(100.4 MHz, CDCl₃) 137.1, 123.6, 74.9, 73.4, 26.0, 25.9,

23.1, 18.4; IR (ﬁlm, KBr) 3399, 2977, 2933, 2917, 1677,

1449, 1379, 1303, 1265, 1222, 1160, 1116, 1040, 1027, 989,

963, 898, 849, 775, 733 cm²¹; GC/MS m/z 144 (M^þ), 127,

111, 97, 93, 86, 77, 71, 59, 55. Anal. Calcd for C₈H₁₆O₂: C,

66.63; H, 11.18. Found C, 66.38; H, 11.39.

7.1.7. Synthesis of 2-cyano-3-(2,2-dimethyl-[1,3]dioxo-

lan-4-yl)acrylic acid methyl ester. It has been performed

according to the Procedure B described above for the related

dimethyl ester using lead tetracetate (12.4 mmol, 5.5 g) and

methyl cyanoacetate (30 mmol, 2.97 g). It give an orange oil

(6.9 g) which was rapidly puriﬁed by column chromato-

graphy (pentane/ethyl acetate: 85/15 (v/v)) to yield the pure

alkylidene malonate (3.49 g, 74%) as a light yellow oil.

[a]²_D⁰¼þ17.0 (c 1.88, CHCl₃); TLC, SiO₂: R_f0.51

(pentane/ether: 70/30). lGC²l, program A, 6.8 min; ¹H

NMR d (400 MHz, CDCl₃) 7.58 (d, 1H, J¼7.6 Hz,

CHvC(CO₂Me)(CN)), 5.07 (m, CH–O), 4.34 (m, 1H,

CH–O), 3.90 (s, 3H, OCH₃), 3.80 (m, 1H, CH–O), 1.50 (s,

3H, CH₃), 1.43 (s, 3H, CH₃); ¹³C NMR d (100.4 MHz,

CDCl₃) 161.0, 159.7, 112.7, 111.5, 109.9, 73.6, 68.2, 53.5,

26.3, 25.3 IR (ﬁlm, KBr) 2992, 2959, 2889, 2235, 1740,

1637, 1439, 1376, 1329, 1309, 1261, 1225, 1151, 1060,

1034, 963, 921, 843, 762, 513 cm²¹; GC/MS m/z 212

(M^þþ1), 196, 181, 154, 136, 123, 108, 94, 72, 59, 52. The

analytical data are in agreement with that reported in the

literature.¹⁶

7.1.10. Synthesis of 2,2-dimethyl-4-(2-methyl-propenyl)-

[1,3]dioxolane. p-Toluenesulfonic acid (50 mg) and 2,2-

dimethoxypropane (50 ml) were added under an atmosphere

of argon to a solution of 2,4-dimethyl-hex-4-ene-2,3-(R)-

diol (12 mmol, 1.74 g) in acetone (A.C.S reagent, 50 ml)

maintained at 20 8C. The mixture was stirred at 20 8C for

12 h. A saturated sodium bicarbonate solution (5 ml) was

then added and the mixture was extracted with diethyl ether

(3£70 ml). Organic layers were dried (MgSO₄) and the

solvents were removed under reduced pressure to give the

pure acetonide (2.2 g, 99%) as a colorless oil. [a]²_D⁰¼23.14

(c 2.96, CHCl₃); TLC, SiO₂: R_f0.33 (pentane/ether: 90/10).

1

lGC²l, program A, 3.3 min; H NMR d (400 MHz, CDCl₃)

5.21 (d, 1H, J¼8.8 Hz, CHvCMe₂), 4.50 (d, 1H, J¼8.9 Hz,

7.1.8. Synthesis of 2-(2,2-dimethyl-[1,3]dioxolan-4-

CH–O), 1.80 (s, 3H, CH₃), 1.76 (s, 3H, CH₃), 1.46 (s, 3H,

7650

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

CH₃), 1.39 (s, 3H, CH₃), 1.25 (s, 3H, CH₃), 1.13 (s,

3H, CH₃); ¹³C NMR d (100.4 MHz, CDCl₃) 139.0, 119.4,

80.9, 80.0, 28.3, 26.8, 26.0, 25.5, 23.2, 18.3; IR (ﬁlm, KBr)

2982, 2935, 2889, 1779, 1679, 1454, 1376, 1372, 1311,

1266, 1234, 1217, 1202, 1145, 1121, 1048, 1035, 995,

962, 933, 916, 866, 829, 806, 654 cm²¹; GC/MS m/z

169 (M^þ2CH₃), 126, 111, 109, 97, 84, 67, 59, 51. Anal.

Calcd for C₁₁H₂₀O₂: C, 71.70; H, 10.94. Found C, 71.56;

H, 11.14.

7.1.13. Cyclopropanation of 2-(2,2-dimethyl-[1,3]dioxo-

lan-4-ylmethylene)-malonic acid dimethyl ester. Typical

procedure C, using isopropylidene triphenylphosphorane.

To a well stirred suspension of isopropyltriphenyl-

phosphonium iodide (3.6 mmol, 1.55 g) in anhydrous THF

(8 ml) was added under an atmosphere of argon, dropwise

n-butyllithium (1.6 N in hexane, 3.0 mmol, 1.84 ml) main-

tained at 0 8C. The dark red mixture was then stirred at room

temperature for 0.25 h before addition of the alkylidene

malonate (2.0 mmol, 488 mg) to the solution at 0 8C. After

stirring at this temperature for 1 h, the mixture was stirred at

20 8C for 24 h. Water was added and the mixture was

extracted with diethyl ether (3£50 ml), washed with water

(1£10 ml), with brine (1£10 ml) and dried (MgSO₄). The

solvents were removed under reduced pressure to give

orange oil (1.16 g). The crude material (1.09 g) was puriﬁed

by column chromatography (pentane/ether: 70/30 (v/v)) to

yield the pure cyclopropane-1,1-dicarboxylate (432 mg,

80%) as a colorless oil.

7.1.11. Synthesis of 2,2-5,5-tetramethyl-[1,3]dioxolane-4-

carbaldehyde. 2,2-Dimethyl-4-(2-methyl-propenyl)-[1,3]-

dioxolane (9.8 mmol, 1.8 g) was dissolved in anhydrous

dichloromethane (40 ml) and the mixture was cooled to

278 8C. Ozone was then bubbled for 1 h in the solution.

Methyl sulﬁde (4 ml) was then added, the mixture was

stirred at room temperature overnight and the solvents were

removed under reduced pressure to give aldehyde (2.34 g)

as a light yellow oil. This product was used directly without

puriﬁcation in the Knoevenagel condensation with dimethyl

malonate. ¹H NMR d (400 MHz, CDCl₃) 9.70 (d, 1H,

J¼2.11 Hz, CHvO), 4.10 (d, 1H, J¼2.03 Hz, CH–O), 1.57

(s, 3H, CH₃), 1.45 (s, 3H, CH₃), 1.42 (s, 3H, CH₃), 1.21 (s,

3H, CH₃); ¹³C NMR d (100.4 MHz, CDCl₃) 200.3, 102.1,

86.6, 80.8, 40.4, 27.9, 27.0, 26.7, 23.6; IR (ﬁlm, KBr)

3268, 2985, 2938, 2882, 2731, 2593, 1735, 1465, 1438,

1406, 1374, 1313, 1259, 1233, 1221, 1198, 1130, 1071,

1025, 1004, 953, 916, 893, 862, 828, 813, 735, 701,

666 cm²¹; GC/MS m/z 143 (M^þ2CH₃), 129, 110, 95, 85,

59, 55.

Typical procedure D, using isopropylidene diphenylsulfur-

ane. A solution of LDA 0.55 N (2.10 ml) was added

dropwise under an atmosphere of argon, to a well stirred

mixture of isopropyldiphenylsulfonium tetraﬂuoroborate

(1.2 mmol, 380 mg) and freshly distilled dichloromethane

(1.2 mmol, 102 mg) in anhydrous DME (7 ml) maintained

at 278 8C. The yellow solution was then stirred for 0.3 h at

278 8C. The alkylidene malonate (1.0 mmol, 244 mg),

diluted in DME (1 ml), was added. After stirring for 2 h at

278 8C and 1 h at 20 8C, the mixture was hydrolyzed by the

addition of a saturated aqueous ammonium chloride

solution (5 ml), extracted with diethyl ether (3£50 ml),

washed with brine (1£10 ml) and dried (MgSO₄). The

solvents were removed under reduced pressure to give an

orange oil (442 mg). The crude material (370 mg) was

puriﬁed by column chromatography (pentane/ether: 70/30

(v/v)) to yield the pure cyclopropane-1,1-dicarboxylate

(180 mg, 76%) as a colorless oil. [a]²_D⁰¼þ0.93 (c 1.01,

CHCl₃); TLC, SiO₂: R_f0.6 (pentane/ether: 70/30). lGC²l,

program A, 6.3 min; ¹H NMR d (400 MHz, CDCl₃) 4.16 (m,

1H, CH–O), 3.98 (m, 1H, CH–O), 3.79 (m, 1H, CH–O),

3.73 (s, 6H, 2OCH₃), 1.81 (d, 1H, J¼9.8 Hz, H cyclo-

propane), 1.45 (s, 3H, CH₃), 1.34 (s, 3H, CH₃), 1.31 (s, 3H,

CH₃), 1.30 (s, 3H, CH₃); ¹³C NMR d (100.4 MHz, CDCl₃)

168.7, 167.6, 109.2, 73.3, 69.1, 52.6, 52.3, 38.8, 30.9, 26.9,

25.5, 22.0, 18.0; IR (ﬁlm, KBr) 2998, 2956, 2878, 1733,

1437, 1380, 1291, 1250, 1159, 1123, 1112, 1067, 1032, 996,

947, 917, 852, 823, 791, 735, 649 cm²¹; GC/MS m/z 271

(M^þ2CH₃), 211, 185, 153, 125, 101, 59. Anal. Calcd for

C₁₄H₂₂O₆: C, 58.73; H, 7.74. Found C, 58.62; H, 7.97.

7.1.12. Synthesis of 2-(2,2-5,5-tetramethyl-[1,3]dioxo-

lane-4-ylmethylene)-malonic acid dimethyl ester.

Titanium (IV) chloride (18 mmol, 2.03 g) was added

dropwise under an atmosphere of argon, to anhydrous

THF (57 ml) maintained at 278 8C. The resulting yellow

suspension was kept at this temperature for 0.25 h. A

mixture of dimethyl malonate (27 mmol, 3.6 g), 2,2-5,5-

tetramethyl-[1,3]dioxolane-4-carbaldehyde (9 mmol, 2.3 g)

and pyridine (36 mmol, 2.85 ml) was then added dropwise

to the yellow suspension. The resulting orange mixture was

stirred at 20 8C for 48 h before the reaction was quenched

with a saturated ammonium chloride solution (50 ml). The

aqueous phase was extracted with diethyl ether (3£80 ml).

The combined organic layers were washed with brine

(20 ml), dried (MgSO₄) and the solvents were removed

under reduced pressure to give 5.11 g of brown oil. The

crude product (4.98 g) was puriﬁed by distillation (bp

110 8C, 0.1 mm Hg) to yield the pure alkylidene malonate

(2.11 g, 88%) as a yellow oil. [a]²_D⁰¼22.66 (c 1.43, CHCl₃);

TLC, SiO₂: R_f0.43 (pentane/ether: 80/20). lGC²l, program

1

A, 8.3 min; H NMR d (400 MHz, CDCl₃) 6.89 (d, 1H,

7.1.14. Cyclopropanation of 2-(2,2-dimethyl-[1,3]dioxo-

lan-4-ylmethylene)-malonic acid di-tert-butyl ester.

According to procedure C. Using isopropyltriphenyl-

phosphonium iodide (3.6 mmol, 1.55 g) and the alkylidene

malonate (2.0 mmol, 656 mg), gives an orange oil (1.56 g)

puriﬁed by column chromatography (pentane/ether: 70/30

(v/v)) to yield the pure cyclopropane-1,1-dicarboxylate

(638 mg, 90%).

J¼6.6 Hz, CHvC(CO₂Me)₂), 4.56 (d, 1H, J¼6.7 Hz, CH–

O), 3.84 (s, 3H, OCH₃), 3.82 (s, 3H, OCH₃), 1.47 (s, 3H,

CH₃), 1.37 (m, 3H, CH₃), 1.36 (s, 3H, CH₃), 1.17 (s, 3H,

CH₃); ¹³C NMR d (100.4 MHz, CDCl₃) 165.4, 163.7, 142.0,

129.5, 109.0, 82.0, 80.7, 52.6, 52.3, 28.1, 27.0, 26.1, 23.9;

IR (ﬁlm, KBr) 2985, 2957, 2850, 1735, 1659, 1559, 1438,

1372, 1338, 1252, 1224, 1199, 1147, 1119, 1075, 1040,

1017, 1001, 944, 904, 862, 672 cm²¹; GC/MS m/z 257

(M^þ2CH₃), 225, 214, 197, 183, 156, 139, 125, 110, 95, 73,

59, 53. Anal. Calcd for C₁₃H₂₀O₆: C, 57.34; H, 7.40. Found

C, 56.55; H, 7.38.

According to procedure D. Using isopropyldiphenyl-

sulfonium tetraﬂuoroborate (1.2 mmol, 380 mg). The alkyl-

idene malonate (1.0 mmol, 328 mg) to give an orange oil

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

7651

(629 mg) puriﬁed by column chromatography (pentane/

ether: 90/10 (v/v)) to yield the pure cyclopropane-1,1-

dicarboxylate (261 mg, 78%) as a colorless oil.

515 cm²¹; GC/MS m/z 313 (M^þ2CH₃), 257, 227, 215, 197,

171, 153, 139, 101, 93, 73, 57. Anal. Calcd for C₁₇H₂₈O₆: C,

62.18; H, 8.60. Found C, 62.24; H, 8.56.

According to procedure E. A solution of potassium tert-

butoxide (0.7 mmol, 79 mg) in anhydrous THF was added

dropwise under an atmosphere of argon, to a well stirred

mixture of isopropyldiphenylsulfonium tetraﬂuoroborate

(0.75 mmol, 237 mg) and alkylidene malonate (0.5 mmol,

164 mg) in anhydrous THF maintained at 278 8C. After

stirring the light yellow solution for 1 h at 278 8C and 1 h at

20 8C, the mixture was hydrolyzed by the addition of water

(10 ml), extracted with diethyl ether (3£30 ml) and dried

(MgSO₄). The solvents were removed under reduced

pressure to give orange oil (308 mg). The crude material

(272 mg) was puriﬁed by column chromatography

(pentane/ether: 85/15 (v/v)) to yield the pure cyclo-

propane-1,1-dicarboxylate (96 mg, 58%) as a colorless oil.

[a]²_D⁰¼þ3.00 (c 1.40, CHCl₃); TLC, SiO₂: R_f0.42

(pentane/ether: 80/20). lGC²l, program A, 11.4 min; ¹H

NMR d (400 MHz, CDCl₃) 4.15 (m, 1H, CH–O), 3.95 (m,

1H, CH–O), 3.80 (m, 1H, CH–O), 1.68 (d, 1H, J¼9.8 Hz,

H cyclopropane), 1.46 (s, 18H, 2O(CH₃)₃), 1.45 (s, 3H,

CH₃), 1.35 (s, 3H, CH₃), 1.34 (s, 3H, CH₃), 1.24 (s, 3H,

CH₃); ¹³C NMR d (100.4 MHz, CDCl₃) 167.7, 166.6, 109.1,

81.7, 81.4, 73.7, 69.3, 37.2, 29.6, 28.0, 27.0, 26.9, 25.6,

22.1, 17.8; IR (ﬁlm, KBr) 2994, 2978, 2939, 2873, 2362,

1726, 1464, 1395, 1370, 1338, 1291, 1258, 1218, 1156,

1129, 1113, 1066, 1018, 978, 947, 921, 909, 859, 815, 790,

737, 667 cm²¹; GC/MS m/z 339, 315, 299, 287, 259, 229,

215, 201, 183, 165, 157. Anal. Calcd for C₂₀H₃₄O₆: C,

64.84; H, 9.25. Found C, 64.83; H, 9.19.

7.1.16. Cyclopropanation of 2-cyano-3-(2,2-dimethyl-

[1,3]dioxolan-4-yl)-acrylic acid methyl ester. According

to procedure C. Using isopropyltriphenylphosphonium

iodide (2.7 mmol, 1.17 g) and the a-cyanoacrylate

(1.5 mmol, 317 mg) gives an orange oil (721 mg). The

crude material (704 mg) puriﬁed by column chromato-

graphy (pentane/ether: 80/20 (v/v)) yields two pure

cyclopropane derivatives: Re compound (colorless oil,

240 mg, 67%) and Si compound (white solid, 29 mg, 8%).

Overall yield: 75%.

According to procedure D. Using isopropyldiphenylsul-

fonium tetraﬂuoroborate (1.2 mmol, 380 mg) and the

a-cyanoacrylate (1.0 mmol, 211 mg), gives an orange oil

(612 mg). The crude material (582 mg) was puriﬁed by

column chromatography (pentane/ether: 70/30 (v/v)) to

yield two pure cyclopropane derivatives. Re compound

(colorless oil, 161 mg, 67%) and Si compound (white solid,

19 mg, 8%). Overall yield: 75%. Re compound:

[a]²_D⁰¼þ11.13 (c 0.72, CHCl₃); TLC, SiO₂: R_f0.33

(pentane/ether: 80/20). lGC²l, program A, 8.0 min; ¹H

NMR d (400 MHz, CDCl₃) 4.23 (m, 1H, CH–O), 4.05 (m,

1H, CH–O), 3.83 (s, 1H, OCH₃), 3.81 (m, 1H, CH–O), 2.12

(d, 1H, J¼10.4 Hz, H cyclopropane), 1.54 (s, 3H, CH₃),

1.47 (s, 3H, CH₃), 1.37 (s, 3H, CH₃), 1.35 (s, 3H, CH₃); ¹³

C

NMR d (100.4 MHz, CDCl₃) 165.8, 115.9, 109.8, 72.8,

68.3, 53.2, 39.9, 36.4, 27.8, 26.6, 25.2, 20.2, 18.4; IR (ﬁlm,

KBr) 2982, 2938, 2865, 2245, 1740, 1460, 1436, 1295,

1233, 1167, 1113, 1073, 1046, 999, 936, 915, 871, 844, 786,

689, 613, 552 cm²¹; GC/MS m/z 238 (M^þ2CH₃), 196, 178,

164, 152, 137, 120, 101, 93, 73, 59, 53. Anal. Calcd for

C₁₃H₁₉O₄N: C, 61.,64; H, 7.56; N, 5.53. Found C, 61.64; H,

7.58; N, 5.55. Si compound: [a]²_D⁰¼212.13 (c 0.80, CHCl₃);

TLC, SiO₂: R_f0.19 (pentane/ether: 80/20). lGC²l, program

7.1.15. Cyclopropanation of 2-(2,2-dimethyl-[1,3]dioxo-

lan-4-ylmethylene)-malonic acid tert-butyl ester

dimethyl ester. According to procedure C. Using iso-

propyltriphenylphosphonium iodide (2.7 mmol, 1.17 g) and

the alkylidene malonate (1.5 mmol, 429 mg) to give orange

oil (923 mg). The crude material (867 mg) was puriﬁed by

column chromatography (pentane/ether: 70/30 (v/v)) to

yield a intractable 59/41 mixture of cyclopropane-1,1-

dicarboxylates (388 mg, 84%) as a colorless oil.

1

A, 8.1 min; mp 97 8C. H NMR d (400 MHz, CDCl₃) 4.13

(m, 1H, CH–O), 4.07 (m, 1H, CH–O), 3.82 (s, 1H, OCH₃),

3.74 (m, 1H, CH–O), 2.16 (d, 1H, J¼9.6 Hz, H cyclo-

propane), 1.46 (s, 3H, CH₃), 1.40 (s, 3H, CH₃), 1.38 (s, 3H,

CH₃), 1.32 (s, 3H, CH₃); ¹³C NMR d (100.4 MHz, CDCl₃)

166.2, 116.1, 110.0, 73.1, 68.2, 53.4, 41.0, 35.2, 29.6, 26.7,

25.4, 20.5, 19.2; IR (ﬁlm, KBr) 3034, 2998, 2982, 2938,

2865, 2369, 2345, 2245, 1740, 1460, 1436, 1380, 1375,

1325, 1294, 1233, 1167, 1113, 1073, 1046, 999, 936, 915,

871, 844, 786, 689, 613, 552 cm²¹; GC/MS m/z 238

(M^þ2CH₃), 196, 178, 164, 152, 137, 120, 101, 93, 72,

59, 53. Anal. Calcd for C₁₃H₁₉O₄N: C, 61.64; H, 7.56; N,

5.53. Found C, 61.60; H, 7.75; N, 5.49.

According to procedure D. Using isopropyldiphenylsul-

fonium tetraﬂuoroborate (1.2 mmol, 380 mg) and the

alkylidene malonate (1.0 mmol, 286 mg), gives an orange

oil (627 mg). The crude material (583 mg) puriﬁed by

column chromatography (pentane/ether: 80/20 (v/v)) to

yield a intractable 55/45 mixture of cyclopropane-1,1-

dicarboxylates (235 mg, 77%) as a colorless oil. TLC, SiO₂:

R_f0.8 (pentane/ether: 80/20). lGC²l, program A, 9.8 and

9.9 min; ¹H NMR d (400 MHz, CDCl₃) 4.21–4.14 (m, CH–

O ZþE), 4.02–3.94 (m, CH–O ZþE), 3.84–2.78 (m, CH–

O ZþE), 3.73 (s, OCH₃E), 3.72 (s, OCH₃Z), 1.79–1.74 (d,

J¼9, 4, 9.0 Hz, H cyclopropane ZþE), 1.47 (s, OC(CH₃)₃

E), 1.46 (s, 2CH₃), 1.45 (s, OC(CH₃)₃Z), 1.36 (s, CH₃), 1.35

(s, 2CH₃), 1.34 (s, CH₃), 1.30 (s, CH₃), 1.28 (s, CH₃); ¹³C

NMR d (100.4 MHz, CDCl₃) 169.4, 168.3, 167.3, 166.2,

109.2, 81.9, 81.8, 73.6, 73.4, 69, 3, 69.2, 52.4, 52.1, 42.7,

30.3, 30.2, 27.9, 27.8, 27.0, 26.9, 25.5, 22.1, 22.0, 18.1,

17.8; IR (ﬁlm, KBr) 2985, 2956, 2937, 2877, 1347, 1731,

1458, 1437, 1393, 1371, 1291, 1253, 1222, 1209, 1160,

1125, 1112, 1067, 997, 949, 917, 849, 809, 791, 740, 588,

7.1.17. Cyclopropanation of 2-(2,2-dimethyl-[1,3]dioxo-

lan-4-ylmethylene)-malononitrile.

According

to

procedure C. Using isopropyltriphenylphosphonium iodide

(18.0 mmol, 7.8 g) and the alkylidene malononitrile

(prepared just before as previously described from

10.0 mmol of 2,3-O-isopropylidene-^D-glyceraldehyde,

gives an brown oil (3.2 g). The crude material was puriﬁed

by column chromatography (pentane/ether: 70/30 (v/v)) to

yield two pure cyclopropane derivatives as white solids. Re

compound (246 mg, 11%) and Si compound (396 mg, 18%).

Overall yield over two steps: 29%.

7652

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

According to procedure D. Using isopropyldiphenylsul-

fonium tetraﬂuoroborate (6.0 mmol, 1.9 g) and the alkyl-

idene malononitrile (prepared just before as previously

described from 5.0 mmol of 2,3-O-isopropylidene-^D-glycer-

aldehyde, gives an brown oil (1.31 g). The crude material

was puriﬁed by column chromatography (pentane/ether:

70/30 (v/v)) to yield two pure cyclopropane derivatives as

white solids: Re compound (145 mg, 13%) and the Si

compound (218 mg, 20%). Overall yield over two steps:

33%. Re compound: [a]_D²⁰¼27.75 (c 0.96, CHCl₃); TLC,

SiO₂: R_f0.38 (pentane/ether: 50/50). lGC²l, program A,

7.5 min; mp 118 8C. ¹H NMR d (400 MHz, CDCl₃) 4.15 (m,

1H, CH–O), 3.99 (m, 1H, CH–O), 3.77 (m, 1H, CH–O),

1.90 (d, 1H, J¼9.7 Hz, H cyclopropane), 1.51 (s, 3H, CH₃),

1169, 1126, 1109, 1077, 1052, 1032, 1001, 962, 937, 912,

891, 861, 824, 800, 753 cm²¹; GC/MS m/z 299 (M^þ2CH₃),

256, 225, 185, 153, 139, 73, 59. Anal. Calcd for C₁₆H₂₆O₆:

C, 61.13; H, 8.34. Found C, 60.97; H, 8.54. Re compound:

[a]²_D⁰¼29.05 (c 1.21, CHCl₃); TLC, SiO₂: R_f0.48

(pentane/ether: 80/20). lGC²l, program A, 9.1 min; mp

56 8C. ¹H NMR d (400 MHz, CDCl₃) 3.82 (d, 1H,

J¼9.5 Hz, CH–O), 3.76 (s, 3H, OCH₃), 3.75 (s, 3H,

OCH₃), 1.89 (d, 1H, J¼9.7 Hz, H cyclopropane), 1.46 (s,

3H, CH₃), 1.41 (s, 3H, CH₃), 1.32 (s, 3H, CH₃), 1.30 (s, 3H,

CH₃), 1.25 (s, 3H, CH₃), 1.21 (s, 3H, CH₃); ¹³C NMR d

(100.4 MHz, CDCl₃) 169.1, 80.2, 79.2, 52.6, 52.2, 35.6,

30.3, 28.5, 26.8, 26.5, 23.7, 23.5, 18.2; IR (ﬁlm, KBr)

2985, 2957, 2938, 1729, 1462, 1440, 1429, 1380,

1370, 1350, 1301, 1246, 1215, 1192, 1109, 1182, 1168,

992, 962, 935, 914, 889, 861, 828, 815, 752 cm²¹; GC/MS

m/z 299 (M^þ2CH₃), 225, 185, 153, 139, 100, 73, 59. Anal.

Calcd for C₁₆H₂₆O₆: C, 61.13; H, 8.34. Found C, 60.98; H,

8.37.

1.49 (s, 3H, CH₃), 1.41 (s, 3H, CH₃), 1.40 (s, 3H, CH₃); ¹³

C

NMR d (100.4 MHz, CDCl₃) 114.1, 112.5, 110.5, 72.3,

67.8, 43.3, 33.8, 26.7, 25.2, 24.1, 17.4, 14.9; IR (ﬁlm, KBr)

2997, 2943, 2904, 2870, 2243, 1477, 1457, 1421, 1383,

1338, 1263, 1226, 1210, 1153, 1113, 1063, 1048, 1003, 978,

916, 839, 791, 638 cm²¹; GC/MS m/z 221 (M^þþ1), 205,

190, 175, 163, 145, 120, 118, 73, 59, 53. Anal. Calcd for

C₁₂H₁₆O₂N₂: C, 65.43; H, 7.32; N, 12.72. Found C, 65.33;

H, 7.47; N, 12.53. Si compound: [a]²_D⁰¼þ6.9 (c 0.81,

CHCl₃); TLC, SiO₂: R_f0.4 (pentane/ether: 50/50). lGC²l,

7.1.19. Synthesis of the authentic sample of 3-(2,2-

dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclo-

propane-1,1-dicarboxylic acid dimethyl ester from

methyl 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-

dimethyl-cyclopropane-1-carboxylate.^5cTo a well stirred

solution of diisopropylamine (1.5 mmol, 151 mg) in

anhydrous tetrahydrofuran (2 ml) was added under an

atmosphere of argon, n-butyllithium (1.6 N in hexane,

1.2 mmol, 0.75 ml) maintained at 0 8C. The mixture was

stirred at 0 8C for 15 min and then cooled to 278 8C before

1

program A, 6.5 min; mp 117 8C. H NMR d (400 MHz,

CDCl₃) 4.22 (m, 1H, CH–O), 3.93–3.86 (m, 2H, 2CH–O),

1.82 (d, 1H, J¼9.3 Hz, H cyclopropane), 1.46 (s, 6H,

2CH₃), 1.40 (s, 3H, CH₃), 1.30 (s, 3H, CH₃); ¹³C NMR d

(100.4 MHz, CDCl₃) 113.9, 112.6, 110.5, 72.5, 68.3, 42.5,

35.2, 26.9, 25.2, 24.0, 17.0, 13.2; IR (ﬁlm, KBr) 3034,

2986, 2937, 2884, 2244, 1481, 1456, 1378, 1260, 1222,

1164, 1075, 1055, 992, 974, 931, 858, 834, 793, 720,

691, 649 cm²¹; GC/MS m/z 205, 190, 175, 163, 145,

128, 118, 101, 73, 59, 53. Anal. Calcd for C₁₂H₁₆O₂N_2:

C, 65.43; H, 7.32; N, 12.72. Found C, 65.93; H, 7.52; N,

12.11.

addition

dimethyl-cyclopropane-1-methylcarboxylate

of

3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-

(1.0 mmol,

228 mg) previously prepared as the well known pro-

cedure.^5cThe yellow solution was stirred at 278 8C for

45 min and methyl chloro formate (1.5 mmol, 142 mg) was

then added dropwise. After stirring at this temperature for

2 h, the mixture was hydrolyzed by addition of water (5 ml),

extracted with diethyl ether (4£20 ml) and dried (MgSO₄).

The solvents were removed under reduced pressure to give

313 mg of crude material. 173 mg were puriﬁed by

column chromatography (pentane/ether: 80/20) to yield

the pure 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-

cyclopropane-1,1-dicarboxylic acid dimethyl ester (131 mg,

82%). Spectral and analytical data are in agreement with the

authentic sample previously described in this paper.

7.1.18. Cyclopropanation of 2-(2,2-5,5-tetramethyl-

[1,3]dioxolan-4-ylmethylene)-malonic acid dimethyl

ester. According to procedure C. Using isopropyltriphenyl-

phosphonium iodide (1.94 mmol, 838 mg) and the alkyl-

idene malonate (1.08 mmol, 293 mg), gives yellow oil

(1.41 g). The crude material (1.37 g) was puriﬁed by column

chromatography (pentane/ether: 70/30 (v/v)) to yield a

mixture of cyclopropane-1,1-dicarboxylates (269 mg, 82%)

as a colorless oil (95/5 Si/Re compounds).

7.1.20. Transesteriﬁcation of 3-(2,2-dimethyl-[1,3]dioxo-

lan-4-yl)-2,2-dimethyl-cyclopropane-1,1-dicarboxylic

acid tert-butyl ester methyl ester with potassium tert-

butoxide. To a well stirred solution of potassium tert-

butoxide (2.8 mmol, 314 mg) in anhydrous THF (3.7 ml)

was added under an atmosphere of argon, the 3-(2,2-

dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-

1,1-dicarboxylic acid dimethyl ester (0.91 mmol, 300 mg)

maintained at 20 8C. The mixture was then stirred 2 h at

room temperature. Water was added (5 ml) and the mixture

was extracted with diethyl ether (3£30 ml) and dried

(MgSO₄). The solvents were removed under reduced

pressure to give 392 mg of crude material. 337 mg were

puriﬁed by thin layer chromatography (pentane/ether:

90/10) to yield the pure 3-(2,2-dimethyl-[1,3]dioxolan-4-

yl)-2,2-dimethyl-cyclopropane-1,1-dicarboxylic acid di-

tert-butyl ester (274 mg, 95%). Spectral and analytical

According to procedure D. Using isopropyldiphenylsul-

fonium tetraﬂuoroborate (1.2 mmol, 380 mg) and the

alkylidene malonate, gives brown oil (639 mg). The crude

material (602 mg) was puriﬁed by column chromatography

(pentane/ether: 80/20 (v/v)) to yield the pure Si compound

(224 mg, 76%) as a colorless oil. Si compound:

[a]²_D⁰¼þ23.90 (c 0.70, CHCl₃); TLC, SiO₂: R_f0.47

(pentane/ether: 80/20). lGC²l, program A, 9.3 min; ¹H

NMR d (400 MHz, CDCl₃) 3.88 (d, 1H, J¼10.2 Hz,

CH–O), 3.74 (s, 3H, OCH₃), 3.70 (s, 3H, OCH₃), 1.84 (d,

1H, J¼10.4 Hz, H cyclopropane), 1.44 (s, 3H, CH₃), 1.43 (s,

3H, CH₃), 1.34 (s, 3H, CH₃), 1.31 (s, 3H, CH₃), 1.24 (s, 3H,

CH₃), 1.22 (s, 3H, CH₃); ¹³C NMR d (100.4 MHz, CDCl₃)

169.2, 168.2, 79.1, 52.6, 52.2, 35.1, 30.6, 28.9, 27.2, 26.4,

23.8, 23.7, 16.7; IR (ﬁlm, KBr) 2982, 2956, 2938, 2878,

1733, 1461, 1437, 1377, 1346, 1291, 1250, 1216, 1201,

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

7653

data are in agreement with the authentic sample previously

described in this paper.

6,6-dimethyl-2-oxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxyl-

ate (316 mg, 89%) as a colorless oil. [a]²_D⁰¼221.86 (c 2.20,

CHCl₃); TLC, SiO₂: R_f0.51 (pentane/ether: 0/100). lGC²l,

program A, 6.1 min; d_H(400 MHz, CDCl₃) 4.81 (m, 1H,

CH–O), 3.98–3.73 (br, 2H, 2CH–OH), 3.82 (s, 3H, OCH₃),

2.52 (d, J¼4.4 Hz, 1H, H cyclopropane), 2.40 (br, 1H, OH),

1.41 (s, 3H, CH₃), 1.31 (s, 3H, CH₃); ¹³C NMR d (100.4 MHz,

CDCl₃) 169.4, 166.0, 79.5, 61.4, 52.8, 42.1, 36.1, 33.4, 22.0,

19.5; IR (ﬁlm, KBr) 3440, 2999, 2958, 2883, 1770, 1730,

1639, 1441, 1320, 1233, 1196, 936, 897, 871, 804, 730,

638 cm²¹; GC/MS m/z 215 (M^þþ1), 199, 197, 183, 165, 153,

151. Anal. Calcd for C₁₀H₁₄O₅: C, 56.07; H, 6.59. Found C,

55.03; H, 6.87.

7.1.21. Bis-transesteriﬁcation of 3-(2,2-dimethyl-

[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-1,1-

dicarboxylic acid dimethyl ester with potassium tert-

butoxide. To a well stirred solution of potassium tert-

butoxide (20.0 mmol, 2.24 g) in anhydrous THF (16 ml)

was added under an atmosphere of argon, 3-(2,2-dimethyl-

[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-1,1-dicar-

boxylic acid tert-butyl ester methyl ester (4 mmol, 1.15 g)

maintained at 20 8C. The mixture was then stirred for 1.5 h

at room temperature. Water was added (7 ml) and the

mixture was extracted with diethyl ether (3£50 ml) and

dried (MgSO₄). The solvents were removed under reduced

pressure to give 1.52 g of crude material. 1.47 g were

puriﬁed by column chromatography (pentane/ether: 90/10)

to yield the pure 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-

dimethyl-cyclopropane-1,1-dicarboxylic acid di-tert-butyl

ester (1.21 g, 92%). Spectral and analytical data are in

agreement with the authentic sample previously described

in this paper. Acid cleavage of the dioxolane ring of 3-(2,2-

dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-

1,1-dicarboxylic acid dimethyl ester: (HCl 10%) which exist

at the smaller/MeOH, 1.5 h at 20 8C. 10% Aqueous

hydrochloric acid (3.0 ml) was added to a solution of

cyclopropane-1,1-dicarboxylate (2.0 mmol, 572 mg) in

methanol (10 ml). The mixture was then stirred for 1.5 h

at room temperature and the solvents were rapidly removed

under reduced pressure. The residue was then solved with

ethyl acetate (100 ml) and the solution was ﬁltered through a

mixture of sodium bicarbonate and magnesium sulfate. The

solvents were removed under reduced pressure to give

556 mg of crude material. 433 mg were puriﬁed by column

chromatography (ethyl acetate) to yield the pure methyl

3-(1,2-dihydroxy-ethyl)-2,2-dimethyl-cyclopropane-1,1-

dicarboxylate (291 mg, 76%) as a colorless oil.

[a]²_D⁰¼214.2 (c 2.43, CHCl₃); TLC, SiO₂: R_f0.25

(pentane/ether: 0/100). ¹H NMR d (400 MHz, CDCl₃)

3.73 (s, 6H, 2OCH₃), 3.84–3.63 (br, 3H, 3CH–O), 1.79 (d,

1H, J¼9.8 Hz, H cyclopropane), 1.37 (s, 3H, CH₃), 1.27 (s,

3H, CH₃); ¹³C NMR d (100.4 MHz, CDCl₃) 169.0, 168.0,

69.3, 66.1, 52.8, 52.5, 37.6, 30.5, 22.7, 17.8; IR (ﬁlm, KBr)

3404, 2956, 2882, 1728, 1438, 1382, 1298, 1256, 1201, 114,

1120, 1033, 993, 950, 923, 874, 823, 804, 747, 722, 695,

600 cm²¹; GC/MS m/z 247 (M^þþ1), 229, 215, 199, 185,

179, 153, 137, 122, 109, 95, 73, 67, 55. Anal. Calcd for

C₁₁H₁₈O₆: C, 53.70; H, 7.04. Found C, 53.46; H, 7.15.

7.1.23. Protection as tert-butyl dimethylsilylether of the

hydroxyl group of methyl 4-hydroxymethyl-6,6-

dimethyl-2-oxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxyl-

ate. Imidazole (18.0 mmol, 1.21 g) was added under

an atmosphere of argon, to a solution of 4-hydroxymethyl-

6,6-dimethyl-2-oxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxylate

(7.2 mmol, 1.55 mg) in anhydrous DMF (10 ml) maintained

at room temperature. The mixture was then stirred for 1 h at

room temperature. Water (10 ml) was added and the mixture

was extracted with ethyl acetate (3£30 ml). Organic layer

was dried (MgSO₄) and the solvents were removed under

reduced pressure to give 2.6 g of crude material which were

puriﬁed by thin layer chromatography (pentane/ether: 70/30

(v/v)) to yield the pure lactone (2.2 g, 92%) as a colorless

oil. TLC, SiO₂: R_f0.48 (pentane/ether: 70/30). lGC²l,

1

program A, 13.5 min; H NMR d (400 MHz, CDCl₃) 4.81

(m, 1H, CH–O), 3.98–3.73 (br, 2H, 2CH–OTBS), 3.82 (s,

3H, OCH₃), 2.49 (d, 1H, J¼4.4 Hz, H cyclopropane), 1.36

(s, 3H, CH₃), 1.27 (s, 3H, CH₃), 0.86 (s, 9H, SiC(CH₃)₃),

0.05 (s, 3H, SiCH₃), 0.04 (s, 3H, SiCH₃); ¹³C NMR d

(100.4 MHz, CDCl₃) 169.4, 166.3, 78.6, 61.5, 52.8, 41.8,

36.4, 33.3, 25.7, 25.6, 21.9, 19.1, 18.1, 25.2, 25.6; IR (ﬁlm,

KBr) 2955, 2932, 2886, 2858, 2363, 1786, 1731, 1464,

1439, 1407, 1391, 1363, 1318, 1276, 1256, 1229, 1195,

1106, 1078, 1051, 1020, 991, 960, 939, 902, 840, 780, 713,

666 cm²¹; GC/MS m/z 329 (M^þþ1), 313, 297, 271, 253,

239, 225, 197, 179, 159, 153. Anal. Calcd for C₁₆H₂₈O₅Si:

C, 58.50; H, 8.59. Found C, 58.44; H, 8.64.

7.1.24. Attempted demethoxycarbonylation of methyl

4-tert-butyl-dimethylsilyloxymethyl-6,6-dimethyl-2-oxo-

3-oxa-bicyclo[3.1.0]hexane-1-carboxylate with

magnesium iodide. To a mixture of magnesium turnings

(0.67 mmol, 16 mg) in anhydrous diethyl ether (3 ml) was

added under an atmosphere of argon, portion wise iodine

(0.54 mmol, 138 mg) maintained at room temperature.

When the color of the iodine disappeared, the ether was

evaporated, the residue was dissolved in anhydrous toluene

(3 ml) and the lactone (0.54 mmol, 176 mg) was added.

After 13 h at 80 8C, the mixture was cooled at room

temperature, a saturated aqueous bicarbonate solution

(10 ml) was added and the layers were separated. The

aqueous layer was acidiﬁed with 10% aqueous HCl and was

extracted with diethyl ether (3£30 ml). Organic layers were

dried (MgSO₄) and the solvents were removed under

reduced pressure to give cyclopropane ring opening

compound (93 mg, 55%) as a brown solid (purity ,90%).

¹H NMR d (400 MHz, CDCl₃) 5.11 (s, H oleﬁnic), 4.96 (s,

H oleﬁnic), 4.69 (m, H vinylic), 4.11 (d, 1H, J¼13 Hz,

7.1.22. Acid cleavage of dioxolane ring of 3-(2,2-

dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclo-

propane-1,1-dicarboxylic acid dimethyl ester. 10%

HCl/MeOH, 50 h at 20 8C. 10% Aqueous hydrochloric

acid (3.0 ml) was added to a solution of cyclopropane 1,1-

dicarboxylate (2.0 mmol, 572 mg) in methanol (10 ml). The

mixture was then stirred for 50 h at room temperature and

the solvents were rapidly removed under reduced pressure.

The residue was then solved with ethyl acetate (100 ml) and

the solution was ﬁltered through a mixture of sodium

bicarbonate and magnesium sulfate. The solvents were

removed under reduced pressure to give 463 mg of crude

material. 382 mg were puriﬁed by column chromatography

(ethyl acetate) to yield the pure methyl 4-hydroxymethyl-

7654

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

CH(CO₂H) cyclopropane), 3.86–3.69 (br, 3H, 2CH–

OTBSþCH–O), 1.87 (s, 3H, CH₃), 0.89 (s, 9H,

SiC(CH₃)₃). 0.08 (s, 3H, SiCH₃), 0.05 (s, 3H, SiCH₃); IR

(ﬁlm, KBr) 2957, 2932, 2860, 1720, 1655, 1390, 1335,

1256, 1161, 1112, 1061, 1037, 1006, 997, 911, 868, 837,

(sþm, 4H, CH₃þH cyclopropane); ¹³C NMR

d

(100.4 MHz, CDCl₃) 172.0, 109.2, 72.4, 69.2, 68.0, 66.4,

51.5, 35.2, 29.3, 28.2, 27.2, 25.7; IR (ﬁlm, KBr) 2988, 2955,

2872, 1728, 1458, 1440, 1378, 1320, 1236, 1205, 1149,

1124, 1097, 1060, 1012, 938, 855, 790, 742 cm²¹; GC/MS

m/z 213 (M^þ2CH₃), 153, 139, 127, 111, 101, 72, 71, 55.

Spectral and analytical data are in agreement with those

reported.⁵

808, 781, 734 cm²¹

.

7.1.25. Decarboxylation of 2,2-dimethyl-cyclopropane-

1,1-dicarboxylic acid methyl ester using the Barton

procedure. Thionyl chloride (1 ml) was added dropwise

under an atmosphere of argon, to a well stirred solution of

carboxylic acid^X(1.37 mmol, 250 mg) in benzene (1 ml)

maintained at 0 8C. One drop of anhydrous DMF was added

and the mixture was stirred at room temperature for 2 h. The

solvents were removed under reduced pressure. The residue

(in 5 ml of benzene) was then added to a solution of

thione^21a(1.51 mmol, 189 mg) in benzene (4 ml) before

introduction of pyridine (0.12 ml). The resulting mixture,

sheltered from sunlight, was stirred at room temperature for

2 h at room temperature, was ﬁltered and the solvents were

removed under reduced pressure. After exposition to

sunlight, the mixture was puriﬁed by thin layer chromato-

graphy (pentane/ether: 60/40) to yield 169 mg of the

pure 2,2-dimethyl-1-(pyridine-2-ylsulfanylcarbonyl)-cyclo-

propanecarboxylic acid methyl ester (169 mg, 66%) as a

colorless liquid. TLC, SiO₂: R_f0.93 (pentane/ether: 60/40).

cis-Cyclopropyl ester. [a]²_D⁰¼þ32.6 (c 12.0, CHCl₃); TLC,

SiO₂: R_f0.68 (pentane/ether: 70/30). lGC²l, program A,

3.6 min; ¹H NMR d (400 MHz, CDCl₃) 4.06 (m, 1H,

CH–O), 3.76–3.68 (br, 2H, 2CH–O), 3.67 (s, 3H, OCH₃),

1.55 (m, 1H, H cyclopropane), 1.45 (s, 3H, CH₃), 1.35 (s,

3H, CH₃), 1.27 (2s, 4H, CH₃þCH(CO₂Me)), 1.26 (s, 3H,

CH₃); IR (ﬁlm, KBr) 2987, 2954, 2876, 1730, 1449, 1377,

1349, 1284, 1234, 1214, 1175, 1117, 1067, 999, 941, 909,

852, 792, 736, 646 cm²¹; GC/MS m/z 213 (M^þ2CH₃), 197,

127, 93, 59. Spectral and analytical data are in agreement

with that reported.^5c

Opened form. TLC, SiO₂: R_f0.78 (pentane/ether: 70/30).

1

lGC²l, program A, 3.9 min; H NMR d (400 MHz, CDCl₃)

4.91 (s, 1H, H oleﬁnic), 4.81 (s, 1H, H oleﬁnic), 4.20 (m,

1H, CH–O), 3.97 (m, 1H, CH–O), 3.83 (s, 3H, OCH₃), 3.80

(m, 1H, CH–O), 2.82 (br, 1H, H vinylic), 2.46 (m, 2H,

CH₂(CO₂Me), 1.80 (s, 3H, CH₃oleﬁnic), 1.45 (s, 3H, CH₃),

1.36 (s, 3H, CH₃); IR (ﬁlm, KBr) 2988, 2952, 2937, 2876,

1727, 1660, 1503, 1384, 1256, 1234, 1213, 1175, 1155,

1

lGC²l, program A, 9.8 min; H NMR d (400 MHz, CDCl₃)

8.41 (m, H aromatic), 7.55 (m, H aromatic), 7.30 (s, H

aromatic), 7.01 (m, H aromatic), 3.71 (s, 3H, OCH₃), 2.05

(d, 1H, J¼4.77 Hz, H cyclopropane), 1.48 (s, 3H, CH₃),

1.29 (s, 3H, CH₃), 1.07 (d, 1H, J¼5.34 Hz, H cyclo-

propane); ¹³C NMR d (100.4 MHz, CDCl₃) 160.7, 149.2,

136.7, 120.9, 119.5, 52.8, 36.0, 30.1, 22.9, 21.1, 20.1; IR

(ﬁlm, KBr) 3047, 2990, 2953, 2931, 2877, 1723, 1605,

1576, 1561, 1452, 1435, 1419, 1377, 1329, 1283, 1243,

1191, 1149, 1128, 1106, 1046, 1017, 998, 986, 966, 944,

874, 854, 759, 726, 667, 619 cm²¹; GC/MS m/z 237 (M^þ),

222, 205, 204, 178, 162, 151, 136, 122, 111, 99, 78, 67, 5.

Anal. Calcd for C₁₂H₁₅NO₂S: C, 60.73; H, 6.37; N, 5.90.

Found C, 60.57; H, 6.59; N, 5.78.

1093, 1063, 1001, 939, 908, 854, 792, 736, 659 cm²¹

;

GC/MS m/z 228 (M^þ), 213, 197 (M^þ2OCH₃), 169, 127, 95,

59. Spectral and analytical data are in agreement with those

reported.

(ii) Using PATP in DMF with a catalytic amount of cesium

carbonate. A solution of PATP (2.0 mmol, 250 mg),

cyclopropane-1,1-dicarboxylate (1.0 mmol, 286 mg) and

cesium carbonate (0.32 mmol, 105 mg) in anhydrous DMF

(9 ml) was stirred under an atmosphere of argon, maintained

at 90 8C for 26 h, then cooled, hydrolyzed with water (10 ml),

extracted with diethyl ether (3£20 ml), washed with water

(10 ml) and dried (MgSO₄). The solvents were removed

under reduced pressure to give 910 mg of crude material

which were puriﬁed by column chromatography (penta-

ne/ether: 80/20 (v/v)) to yield a mixture (155 mg, 68%) of the

two desired cyclopropyl carboxylates (trans/cis: 61/39).

7.1.26. Demethoxycarbonylation of 3-(2,2-dimethyl-

[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclopropane-1,1-

dicarboxylic acid dimethyl ester. (i) Using NaCl in wet

DMSO at 180 8C. A mixture of sodium chloride (4.0 mmol,

236 mg), water (6.0 mmol, 108 mg) and cyclopropane-1,1-

dicarboxylate (3.0 mmol, 858 mg) in DMSO (3 ml) was

stirred at 180 8C for 6 h. After cooling to room temperature,

the mixture was hydrolyzed with water (10 ml) and

extracted with diethyl ether (4£25 ml). Organic layers

were washed with water (10 ml), with brine (10 ml), dried

(MgSO₄) and the solvents were removed under reduced

pressure to give 591 mg of crude material. 522 mg were

puriﬁed by column (pentane/ether: 70/30 (v/v)) to yield a

mixture (449 mg, 73%) of three compounds (trans/cis/open:

27/21/52) as a colorless oil.

(iii) Using Me₄NOAc in DMPU. Tetramethylammonium

acetate (1.1 g) was added under an atmosphere of argon, to a

solution of the cyclopropane-1,1-dicarboxylate (1.0 mmol,

286 mg) in anhydrous DMPU (9 ml) maintained at 20 8C.

The mixture was then stirred for 6 h at 95 8C, cooled,

hydrolyzed with water (10 ml), extracted with diethyl ether

(3£20 ml), washed with water (10 ml) and dried (MgSO₄).

The solvents were removed under reduced pressure to give

850 mg of crude material which were puriﬁed by column

chromatography (pentane/ether: 80/20 (v/v)) to yield a

mixture (180 mg, 79%) of the two desired cyclopropyl

carboxylates (trans/cis: 68/32).

trans-Cyclopropane carboxylate. [a]²_D⁰¼217.8 (c 0.91,

CHCl₃); TLC, SiO₂: R_f0.78 (pentane/ether: 70/30). lGC²l,

program A, 4.1 min; ¹H NMR d (400 MHz, CDCl₃) 4.55 (m,

1H, CH–O), 4.05 (m, 1H, CH–O), 3.66–3.60 (sþm, 4H,

OCH₃þCH–O), 1.56 (d, J¼8.8 Hz, 1H, CH(CO₂Me), 1.45

(s, 3H, CH₃), 1.36 (s, 3H, CH₃), 1.31 (s, 3H, CH₃), 1.24

7.1.27. Acidic cleavage of dioxolane ring of methyl 3-

(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-cyclo-

propane-1-carboxylate. cis-Compound. 10% aqueous

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

7655

hydrochloric acid (3 ml) was added to a solution of

cyclopropane (2.41 mmol, 456 mg) in methanol (10 ml).

The mixture was then stirred for 30 min at room temperature

and the solvents were rapidly removed under reduced

pressure. The residue was then solved with ethyl acetate

(50 ml) and the solution was ﬁltered through a mixture of

sodium bicarbonate and magnesium sulfate. The solvents

were removed under reduced pressure to give 503 mg of

crude material. 481 mg were puriﬁed by column chroma-

tography (pentane/ether: 0/100 (v/v)) to yield the pure

lactone (257 mg, 89%) as a colorless oil. [a]²_D⁰¼268.7 (c

CH(CO₂Me)), 1.23 (2s, 6H, 2CH₃); ¹³C NMR d (100.4 MHz,

CDCl₃) 172.3, 143.8, 128.7, 128.0, 127.1, 87.0, 71.0, 67.3,

51.5, 34.6, 30.9, 26.6, 21.2, 20.7; IR (ﬁlm, KBr) 3468, 3088,

3060, 3027, 2982, 2952, 2928, 2874, 2742, 2081, 1963, 1893,

1816, 1731, 1716, 1598, 1492, 1448, 1375, 1244, 1213, 1171,

1115, 1048, 986, 944, 903, 845, 766, 748, 707, 647, 633,

608 cm²¹; GC/MS m/z 258, 243, 229, 215, 183, 165, 152, 127,

105, 77, 67, 55. Anal. Calcd for C₂₈H₃₀O₄: C, 78.11; H, 7.02.

Found C, 78.00; H, 7.16.

7.1.29. Contrathermodynamic lactonisation of methyl

trans-3-(1-hydroxy-2-trityloxy-ethyl)-2,2-dimethyl-

cyclopropanecarboxylate using potassium tert-butoxide

in benzene. Potassium tert-butoxide (0.44 mmol, 51 mg)

was added under an atmosphere of argon, to a solution of

methyl trans-3-(1-hydroxy-2-trityloxy-ethyl)-2,2-dimethyl-

cyclopropanecarboxylate (0.44 mmol, 169 mg) in anhy-

drous benzene (2 ml) maintained at 20 8C. The resulting

yellow mixture was then stirred for 6 h at 80 8C, cooled and

dichloromethane was added (10 ml). The solution was

hydrolyzed with a saturated aqueous ammonium chloride

solution (5 ml), extracted with dichloromethane (2£10 ml)

and dried (MgSO₄). The solvents were removed under

reduced pressure to give 181 mg of crude material. 152 mg

were puriﬁed by thin layer chromatography (pentane/ether:

60/40 (v/v)) to yield the pure 6,6-dimethyl-4-trityloxy-

methyl-3-oxa-bicyclo[3.1.0]hexan-2-one (138 mg, 79%) as

a white solid. [a]_D²⁰¼257.3 (c 1.24, CHCl₃); TLC, SiO₂: R_f

0.40 (pentane/ether: 70/30). lGC²l, program A, 13.7; mp

101 8C; min; ¹H NMR d (400 MHz, CDCl₃) 7.49–7.25 (m,

15H, OC(C₆H₅)₃), 4.84 (m, H, CH–O), 3.50 (m, 1H,

CH–O), 3.50 (m, 1H, CH–O), 2.27 (br, 1H, OH), 2.00 (br,

2H, 2H cyclopropane), 1.11 (s, 3H, CH₃), 1.03 (s, 3H, CH₃);

¹³C NMR d (100.4 MHz, CDCl₃) 174.4, 143.6, 128.7,

128.0, 127.3, 86.8, 78.9, 62.4, 31.4, 30.9, 26.0, 24.1, 17.4;

IR (ﬁlm, KBr) 3087, 3058, 3031, 2997, 2982, 2960, 2928,

2901, 2873, 1966, 1921, 1875, 1766, 1596, 1561, 1446,

1399, 1380, 1366, 1348, 1314, 1290, 1253, 1217, 1189,

1155, 1134, 1117, 1076, 1028, 991, 937, 899, 864, 848, 820,

771, 755, 703, 647, 631 cm²¹; GC/MS m/z 253, 251, 235,

233. Anal. Calcd for C₂₇H₂₆O₃: C, 81.38; H, 6.58. Found C,

81.33; H, 6.61.

1

1.27, CHCl₃). H NMR d (400 MHz, CDCl₃) 4.78 (m, 1H,

CH–O), 3.98 (m, 1H, CH₂–OH), 3.77 (m, 1H, CH₂-OH),

2.07 (d, 1H, J¼5.4 Hz, CH–CvO), 1.97 (m, 1H, H

cyclopropane), 1.75 (s, 1H, OH), 1.32 (s, 3H, CH₃), 1.17

(s, 3H, CH₃); ¹³C NMR d (100.4 MHz, CDCl₃) 172.2, 68.0,

66.3, 51.4, 33.9, 29.1, 28.6, 25.1; IR (ﬁlm, KBr) 3421, 2960,

1755, 1648, 1456, 1383, 1353, 1313, 1291, 1201, 1119,

1086, 1050, 990, 940, 883, 845, 784 cm²¹; GC/MS m/z

152, 139, 126, 115, 111, 97, 93, 81, 69, 67, 55. The

spectral and analytical data agree with those previously

reported.²⁸

trans-Compound. 10% aqueous hydrochloric acid (3 ml)

was added to a solution of cyclopropane (2.41 mmol,

456 mg) in methanol (12 ml). The mixture was then stirred

for 30 min at room temperature and the solvents were

rapidly removed under reduced pressure. The residue was

then solved with ethyl acetate (50 ml) and the solution was

ﬁltered through a mixture of sodium bicarbonate and

magnesium sulfate. The solvents were removed under

reduced pressure to give 491 mg of crude material which

was puriﬁed by column chromatography (ethyl acetate) to

yield the pure diol (417 mg, 92%) as colorless oil.

[a]²_D⁰¼þ45.0 (c 2.91, CHCl₃). ¹H NMR d (400 MHz,

CDCl₃) 3.67 (s, 3H, OCH₃), 3.74–3.57 (br, 2H, 2CH–O),

3.40 (m, 1H, CH–O), 2.69 (br, 2H, 2OH), 1.51 (m, 1H, H

cyclopropane), 1.40 (d, 1H, J¼9.7 Hz, CH(CO₂Me)), 1.30

(s, 3H, CH₃), 1.25 (s, 3H, CH₃); ¹³C NMR d (100.4 MHz,

CDCl₃) 172.5, 72.4, 66.2, 51.7, 34.2, 30.9, 26.7, 21.2, 20.7;

IR (ﬁlm, KBr) 3407, 2954, 2932, 2877, 2745, 1731, 1449,

1381, 1357, 1288, 1214, 1171, 1117, 1090, 1039, 1014, 998,

969, 938, 909, 874, 843, 778, 733, 653 cm²¹; GC/MS m/z

127, 97, 95, 79, 73, 67, 59, 51. Anal. Calcd for C₉H₁₆O₄: C,

57.43; H, 8.57. Found C, 56.53; H, 8.76.

7.1.30. Removal of trityl group from 6,6-dimethyl-4-

trityloxymethyl-3-oxa-bicyclo[3.1.0]hexan-2-one. 10%

Aqueous hydrochloric acid (0.5 ml) was added to a solution

of lactone (0.25 mmol, 100 mg) in methanol (2 ml). The

mixture was then stirred for 50 min at room temperature,

extracted with diethyl ether (3£10 ml), dried (MgSO₄). The

solvents were removed under reduced pressure to yield the

pure lactone (39 mg, 98%) as a colorless oil. Spectral and

analytical data are in agreement with the product

synthesized previously and the reported data.²⁸

7.1.28. Selective tritylation of the primary hydroxyl

group of methyl trans-3-(2,3-dihydroxy-propyl)-2,2-

dimethyl-cyclopropanecarboxylate.

N,N-4-dimethyl-

amino-N-triphenylmethylpyridinium chloride²⁶(1.28 mmol,

512 mg) was added under an atmosphere of argon, to a

solutionofthediol(1.06 mmol, 200 mg)inanhydrousCH₂Cl₂

(6 ml) maintained at 20 8C. The mixture was then stirred for

22 h at reﬂux, cooled, hydrolyzed with water (5 ml), extracted

with dichloromethane (3£20 ml) and dried (MgSO₄). The

solvents were removed under reduced pressure to give 821 mg

of crude material which were puriﬁed by column chromato-

graphy (pentane/ethyl acetate: 80/20 (v/v)) to yield the pure

tritylether (405 mg, 89%) as a white solid. TLC, SiO₂: R_f0.85

(pentane/ethyl acetate: 80/20). Mp 61 8C. ¹H NMR d

(400 MHz, CDCl₃) 7.46–7.24 (br, 15H, OC(C₆H₅)₃), 3.64

(s, H, OCH₃), 3.31–3.26 (br, 3H, 3CH–O), 2.27 (br, 1H, OH),

1.50 (m, 1H, H cyclopropane), 1.27 (d, 1H, J¼5.5 Hz,

7.1.31. Acid cleavage of dioxolane ring of 2,2-dimethyl-3-

(2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-cyclopropane-

1,1-dicarboxylic acid dimethyl ester. 10% Aqueous

hydrochloric acid (3 ml) was added to a solution of

cyclopropane (2 mmol, 628 mg) in methanol (10 ml). The

mixture was then stirred for 15 min at room temperature and

the solvents were rapidly removed under reduced pressure.

The residue was then solved with ethyl acetate (30 ml) and

the solution was ﬁltered through a mixture of sodium

7656

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

bicarbonate and magnesium sulfate. The solvents were

removed under reduced pressure to give 589 mg of crude

material which was puriﬁed by column chromatography

(pentane/ether: 0/100 (v/v)) to yield pure 4-(1-hydroxy-1-

methyl-ethyl)-6,6-dimethyl-2-oxo-3-oxa-bicyclo[3.1.0]hex-

ane-1-carboxylic acid methyl ester (393 mg, 81%) as a glue.

[a]²_D⁰¼225.7 (c 1.43, CHCl₃); TLC, SiO₂: R_f0.59

(pentane/ether: 0/100). lGC²l, program A, 9.9 min; ¹H

NMR d (400 MHz, CDCl₃) 4.00 (s, 1H, CH–O), 3.82 (s,

3H, OCH₃), 2.50 (s, 1H, H cyclopropane), 1.82 (br, 1H,

OH), 1.32 (s, 3H, CH₃), 1.30 (s, 6H, 2CH₃), 1.29 (s, 3H,

CH₃); ¹³C NMR d (100.4 MHz, CDCl₃) 169.7, 166.2, 100.6,

81.8, 71.6, 52.9, 36.5, 31.8, 25.0, 23.9, 21.2, 16.2; IR (ﬁlm,

KBr) 3500, 3066, 2979, 2936, 2885, 2750, 2106, 1770,

1731, 1646, 1440, 1383, 1334, 1306, 1278, 1234, 1179,

1126, 1106, 1086, 1056, 1027, 1000, 967, 932, 913, 885,

829, 800, 775, 731 cm²¹; GC/MS m/z 243 (M^þþ1), 225,

211 (M^þ2OCH₃), 185, 169, 153, 137, 125, 95, 84, 59, 55.

Anal. Calcd for C₁₂H₁₈O₅: C, 59.49; H, 7.49. Found C,

57.88, H, 7.69.

(10 ml) and dried (MgSO₄). The solvents were removed

under reduced pressure to give 394 mg of crude material

which is puriﬁed by column chromatography (penta-

ne/ether: 90/10) to yield the pure tert-butyl trans-2,2-

dimethyl-3-(2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-cyclo-

propanecarboxylate (222 mg, 93%) as a white solid.

[a]²_D⁰¼þ15.3 (c 0.51, CHCl₃); TLC, SiO₂: R_f0.65

(pentane/ether: 90/10). lGC²l, program A, 8.0 min; mp

66 8C. ¹H NMR d (400 MHz, CDCl₃) 3.56 (d, 1H,

J¼7.1 Hz, CH–O), 1.62 (d, 1H, J¼5.8 Hz, CH–O). 1.46

(s, 9H, O(CH₃)₃), 1.43 (s, 3H, OCH₃), 1.40 (m, 1H, H

cyclopropane), 1.33 (s, 1H, CH₃), 1.29 (s, 1H, CH₃), 1.23

(s, 1H, CH₃), 1.22 (s, 1H, CH₃), 1.21 (s, 1H, CH₃); ¹³C

NMR d (100.4 MHz, CDCl₃) 220.4, 82.0, 31.8, 31.0,

29.6, 28.5, 28.2, 27.1, 26.3, 25.8, 23.5, 22.1, 20.6; IR

(ﬁlm, KBr) 2981, 2935, 2871, 1719, 1460, 1368, 1289,

1268, 1234, 1219, 1201, 1151, 1117, 1067, 1041, 1019,

1002, 917, 844, 772 cm²¹; GC/MS m/z 283 (M^þ2CH₃),

242, 225, 184, 149, 139, 123, 100, 83, 59.57. Anal. Calcd for

C₁₇H₃₀O₄: C, 68.42; H, 10.13. Found C, 67.55; H, 10.15.

7.1.32. Demethoxycarbonylation of 2,2-dimethyl-3-

(2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-cyclopropane-

1,1-dicarboxylic acid dimethyl ester. Tetramethyl-

ammonium acetate (1.6 g) was added under an atmosphere

of argon, to a solution of the 2,2-dimethyl-3-(2,2,5,

5-tetramethyl-[1,3]dioxolan-4-yl)-cyclopropane-1,1-dicar-

boxylic acid dimethyl ester (1.6 mmol, 502 mg) in anhy-

drous HMPA (14 ml) maintained at 20 8C. The mixture was

then stirred for 6 h at 95 8C, cooled, hydrolyzed with water

(10 ml), extracted with diethyl ether (4£30 ml). Organic

layers were washed with water (2£10 ml) and dried

(MgSO₄). The solvents were removed under reduced

pressure to give 655 mg of crude material. 612 mg were

puriﬁed by column chromatography (pentane/ether: 80/20

(v/v)) to yield a mixture of the desired cyclopropyl

carboxylates (81/19 trans/cis, 301 mg, 74%) as a colorless

oil. [a]²_D⁰¼225.7 (c 1.43, CHCl₃); TLC, SiO₂: R_f0.51

and 0.47 (pentane/ether: 0/100). lGC²l, program A, 6.6

and 6.7 min; ¹H NMR d (400 MHz, CDCl₃) 4.30 (s, CH–O

cis), 3.70 (s, OCH₃trans), 3.68 (s, OCH₃trans), 3.56

(d, J¼5.2 Hz, CH–O trans), 1.72 (d, J¼8.8 Hz, CH(CO₂-

Me) cis), 1.70 (d, J¼5.2 Hz, CH(CO₂Me) trans), 1.51

(mult, H cyclopropane trans), 1.44–1.21 (br, 4CH₃transþ4

CH₃cisþH cyclopropane trans); ¹³C NMR d

(100.4 MHz, CDCl₃) 98.1, 89.1, 82.3, 51.6, 51.3, 31.9,

31.7, 30.8, 28.9, 28.7, 28.5, 27.0, 26.7, 26.3, 26.2, 23.8,

23.6, 22.1, 20.7; IR (ﬁlm, KBr) 2979, 2933, 2871, 1722,

1445, 1433, 1377, 1314, 1268, 1230, 1220, 1190, 1151,

7.1.34. Synthesis of thionocarbonate from tert-butyl

trans-2,2-dimethyl-3-(2,2,5,5-tetramethyl-[1,3]dioxolan-

4-yl)-cyclopropanecarboxylate. 10% Aqueous hydro-

chloric acid (2 ml) was added to a solution of tert-butyl

trans-2,2-dimethyl-3-(2,2,5,5-tetramethyl-[1,3]dioxolan-4-

yl)-cyclopropanecarboxylate (0.54 mmol, 166 mg) in THF

(3 ml). The mixture was then stirred 4 h at room

temperature and extracted with diethyl ether (4£10 ml).

Organic layers were dried (MgSO₄) and the solvents were

removed under reduced pressure to give 178 mg of crude

diol as a white solid (115 8C). The diol (0.4 mmol,

81 mg) was dissolved in anhydrous diethyl ether (2 ml).

Diazomethane, freshly prepared, was then added drop-

wise to the solution of until disappearance of the yellow

color. The mixture was stirred for 1 h at 20 8C and the

solvents were then removed under reduced pressure to

give 98 mg of crude ester which is used directly in the

next step. N,N-Dimethylaminopyridine (0.41 mmol,

50 mg) and the previous synthesized ester (0.34 mmol,

74 mg) were dissolved under an atmosphere of argon, in

anhydrous dichloromethane (2 ml) maintained at 0 8C.

Thiophosgene (0.82 mmol, 94 mg), diluted by 1 ml of

dichloromethane, was added dropwise to the solution and

the orange mixture was stirred at 0 8C for 12 h. Silicagel

(2 g) was added to the solution and the solvents were

removed under reduced pressure. The resulting solid was

placed on a silicagel column and eluted with a mixture of

pentane/ether (2/8 (v/v)) to give 69 mg of pure thiono-

carbonate (69 mg, 79% over three steps) as a white solid.

[a]²_D⁰¼þ33.5 (c 0.90, CHCl₃); TLC, SiO₂: R_f0.40

(pentane/ether: 60/40). Mp 108 8C; ¹H NMR d

(400 MHz, CDCl₃) 4.10 (d, 1H, J¼10.7 Hz, CH–O),

3.73 (s, 3H, OCH₃); 1.71 (m, 1H, H cyclopropane); 1.57

(s, 3H, CH₃); 1.50 (s, 3H, CH₃); 1.48 (d, 1H, J¼5.6 Hz,

CH(CO₂Me)); 1.32 (s, 3H, CH₃), 1.29 (s, 3H, CH₃); ¹³C

NMR d (100.4 MHz, CDCl₃) 190.1, 170.7, 89.3, 89.0,

52.1, 30.6, 28.9, 26.3, 21.6, 21.1, 19.6; IR (ﬁlm, KBr)

2989, 2963, 2932, 1733, 1465, 1385, 1326, 1299, 1275,

1251, 1221, 1196, 1180, 1113, 1003, 975, 934, 914, 865,

842, 807, 774, 735, 664 cm²¹; GC/MS m/z 127, 121, 105,

99, 91, 85, 79, 73, 67. Anal. Calcd for C₁₂H₁₈O₄S: C,

55.79; H, 7.02. Found C, 55.72; H, 7.13.

1129, 1118, 1095, 1070, 1039, 1006, 934, 729 cm²¹

;

GC/MS m/z 241, 198, 181, 149, 139, 100, 84, 59. Anal.

Calcd for C₁₄H₂₅O₄: C, 65.60; H, 9.44. Found C, 65.52; H,

9.61.

7.1.33. Synthesis of tert-butyl trans-2,2-dimethyl-3-

(2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-cyclopropane-

carboxylate. To a well stirred solution of potassium tert-

butoxide (1.6 mmol, 180 mg) in anhydrous THF (4 ml) was

added under an atmosphere of argon, the mixture of

cyclopropanes and (0.8 mmol, 204 mg) maintained at

20 8C. The mixture was then stirred for 2 h at room

temperature. Water was added (5 ml) and the mixture was

extracted with diethyl ether (3£30 ml), washed with water

A. Krief, A. Froidbise / Tetrahedron 60 (2004) 7637–7658

7657

Froidbise, A.; Krief, A.; Evrard, G. Acta Crystallogr. Sect. C

1998, 54, 834.

7.1.35. Synthesis of (1R) trans-chrysanthemate by

reduction of thionocarbonate. Thionocarbonate

7. Mulzer, J.; Kappert, M. Angew. Chem., Int. Ed. Engl. 1983, 22,

63.

(0.027 mmol, 69 mg) was heated for 6 h at 40 8C in the

presence of diazaphospholidine (0.80 mmol, 155 mg).

After cooling to room temperature, the crude mixture

8. (a) Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B.

Chem. Rev. 1994, 2483. (b) Xu, D.; Crispino, G. A.; Sharpless,

K. B. J. Am. Chem. Soc. 1992, 114, 7570.

was

(pentane/ether: 90/10 (v/v)) to yield the pure methyl

puriﬁed

by

thin

layer

chromatography

9. (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;

Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,

5765. (b) Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Org.

Chem. 1987, 52, 667. (c) Uchiro, H.; Nagasawa, K.; Aiba, Y.;

Kotake, T.; Hasegawa, D.; Kobayashi, S. Tetrahedron Lett.

2001, 42, 4531.

chrysanthemate (44 mg, 89%) as colorless liquid.

20

D lit

[a]²_D⁰¼þ19.7 (c 1.12, CHCl₃) ([a] ¼þ20.7 (c 1.1,

CHCl₃)); TLC, SiO₂: R_f0.80 (pentane/ether: 95/05);

lGC²l, program A, 4.4 min; ¹H NMR d (400 MHz,

CDCl₃) 4.90 (d, 1H, J¼4.8 Hz, H oleﬁnic), 3.69 (s, 3H,

OCH₃); 2.07 (m, 1H, H cyclopropane); 1.72 (s, 3H, CH₃

oleﬁnic); 1.71 (s, 3H, CH₃oleﬁnic); 1.40 (d, 1H,

J¼5.4 Hz, CH(CO₂Me)); 1.28 (s, 3H, CH₃), 1.15 (s,

3H, CH₃); IR (ﬁlm, KBr) 2952, 2926, 2881, 1730, 1440,

1411, 1379, 1322, 1285, 1235, 1198, 1165, 1142, 1117,

1083, 1065, 995, 919, 854, 782, 729 cm²¹. Spectral and

analytical data are in agreement with the published

data.⁵⁶

10. (a) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23,

1979. (b) Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc.

1963, 85, 2677. (c) Corey, E. J.; Carey, F. A.; Winter, R. A. E.

J. Am. Chem. Soc. 1965, 87, 934.

11. (a) Krief, A.; Denis, J.-N.; Magnane, R.; van Eenoo, M. Nouv.

J. Chim. 1979, 3, 705. (b) Suzuki, H.; Fuchita, T.; Iwasa, A.;

Mishina, T. Synthesis 1978, 12, 905.

12. (a) Tietze, L. F.; Beifuss, U Comprehensive Organic

Synthesis; Pergamon: Oxford, 1994; Vol. 5. p 341. (b) Jones,

G. Org. React. 1967, 15, 204.

13. (a) Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447.

(b) Debost, J.-L.; Gelas, J.; Horton, D. J. Org. Chem. 1983, 48,

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¨

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Dumont, W.; Pasau, P.; Lecomte, Ph Strain and Its

Application in Organic Chemistry; Kluwer Academic:

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¨

22. (a) Hell, Z.; Toke, L. Synth. Commun. 1996, 26, 2127.

(b) Other conditions tested proved also to be unsuccess-

ful.^23–25

.

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Article Doi

Hemisynthesis of methyl pyrethroates from γ-alkoxy-alkylidene malonates and isopropylidenediphenylsulfurane and isopropylidenetriphenylphosphorane

DOI: 10.1016/j.tet.2004.06.035

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