FR2703687A1 - Catalytic process useful for selectively cleaving a protected functional group and molecules capable of being deprotected according to this process - Google Patents

Abstract

The subject of the present invention is a reagent and a process useful for cleaving a functional group protected, during an organic synthesis, by an alkoxycarbonyl group, from the latter. This reagent is defined in that it comprises: a) an aqueous phase; b) a catalyst comprising at least one group VIII element in the Periodic Table of Elements, the said group VIII element in the Periodic Table being maintained in the aqueous phase by the formation of a complex with at least one water-soluble coordinating agent; c) a water-soluble nucleophilic compound. Application to organic synthesis.

Description

CATALYTIC PROCESS USEFUL FOR CLIVER SELECTIVELY A
PROTECTED FUNCTION AND MOLECULES DEPROTECTABLE ACCORDING TO THIS
PROCESS.

 The subject of the present invention is a reagent and a method useful for cleaving a protected function, on the occasion of an organic synthesis by an alkoxycarbonyl group, with that one. It relates more particularly to the cleavage of such a group whose alkoxyl group has unsaturation in B such as propargyl, benzyl or alkyl groups.

 It is common to protect a molecule by blocking the functions which, under the operating conditions envisaged, would be reactive or deemed to be such by groups qualified as protectors.

 These techniques are particularly useful during peptide synthesis and the most commonly protected functions are acid, alcohol, amine or thiol functions.

Among the most commonly used groups are the group
BOC or terbutyloxycarbonyl, Z or benzyloxyl groups, or even the FMOC group. it should be noted that the allylic structure groups would have been considered potentially very interesting if suitable cleavage means were available.

 The deprotection usually used is lysis in an acidic medium, generally in an anhydrous hydrohalic medium (that is to say with a water content in general of less than 1%, advantageously of 3.0-3, preferably 4).

 This technique, however, has many disadvantages. The cleavage reaction is sometimes slow or requires large excess reagents. The alkoxy groups tend to be carbocation with evolution towards the double bonds when possible, or towards alkylation reactions on the nucleus, which is particularly troublesome in the case of syntheses of peptides whose sequence presents residues. nucleophiles such as aromatic nuclei (tryptophan, tyrosine, phenylalanine, ....) or sulfur (methionine). They can even alkylate the functions being released.

 This technique is either non-selective or gives poor results in the case of alkoxycarbonyl groups having B-unsaturation.

 This is why it has been proposed to cleave the alkoxycarbonyl functions having the above characteristics by means of the metals of column VIII generally complexed by various coordinants.

However, although slightly facilitating the cleavage, this technique has the same disadvantages "mutatis mutandis" as those previously described, in particular alkylation of the nucleophilic functions present in the synthesized molecule.

 Therefore, it is an object of the present invention to provide a method and a reagent that substantially accelerate the kinetics of cleavage.

 Another object of the present invention is to provide a process and a reagent which avoid alkylation reactions of aromatic rings.

 Another object of the present invention is to provide a process and a reagent which avoid the alkylation reactions of functions described as nucleophilic.

 Another object of the present invention is to provide a method useful for the selective cleavage of a molecule at least one function is protected by an allyloxycarbonyl protecting group and at least one function is protected by a protective group distinct from the previous one (either because the allyl group is distinct from the previous one, or it is of another nature). it is therefore a selective cleavage process with respect to the various allyl groups and with respect to the other protecting group.

 These and other objects, which will become apparent, are achieved by the use of a reagent useful for cleaving unsaturated alkyloxycarbonyl functions.

 This cleavage which takes place between the allyl group and the carbonyl function (-CO-) can lead to further breakage thus completing the release of certain functions.

The reagent according to the present invention comprises:
a) an aqueous phase;
b) a catalyst comprising at least one element of column Vlil of the Periodic Table of Elements, said element of column VIII of the Periodic Table being maintained in the aqueous phase by complexing with at least one water-soluble coordinating agent;
c) a water-soluble nucleophilic compound.

 When the substrate and / or the product of arrival are not very soluble in aqueous phase, it is possible to carry out the reaction, or by adding a third solvent B, or in a multiphase system, either without addition, or by adding a solvent A, or by simultaneously adding a third solvent B and solvent A.

 The solvents A are organic solvents chosen so that they dissolve at least 1%, advantageously at least 2%, preferably 5% by weight of the substrate and are sufficiently hydrophobic to not be miscible with water in any proportion. .

It is preferable that the water can dissolve at most 10% of solvent
A, advantageously at most 1%, by weight, even in the presence of the substrate as a third solvent.

 It is preferable that the solvent A can dissolve at most 10% of water, advantageously at most 1% by weight, even in the presence of the substrate as a third solvent.

 Solvents A can be mixtures, including petroleum fractions. Naturally, under the operating conditions, the solvents A must be inert with respect to the substrates and reagents used.

 The preferred families of solvents are chosen from the group consisting of hydrocarbons, aromatic derivatives, ethers, esters and halogenated solvents. If it is desired to recover these solvents, it is desirable that they be less nucleophilic than said nucleophilic compound. so as not to interfere with the reaction unless, of course, said nucleophilic compound is in excess sufficient to act as a (third) solvent.

 As paradigms of these families, halogenated aliphatic derivatives include dichloromethane, dichloro-1,2-ethane, trichloro-1,1,1-ethane, aromatic derivatives toluene and halogenated aromatic esters of ethyl acetate and isopropyl acetate, as ethers, tert-butyl methyl ether and anisole and heavy alcohols, that is to say, answering immiscibility constraints such as specified above.

 For reasons of economy, it is preferable that the solvent A is distillable under atmospheric pressure or under primary or secondary vacuum.

Among the solvents A, it is particularly appropriate to mention those which are phenolic and which are detailed in the French applications of the Applicant filed under N 89/15957 and 91/12524
According to one embodiment of the present invention, when the substrates are not water-soluble, it is then possible to those skilled in the art to add a third solvent B whose role will be to solubilize the substrate in the aqueous phase.

 This third solvent B may be partitioned between aqueous and organic phases when the latter exists, either initially or because of the possible simultaneous use of the solvent A.

It is preferable that the water can dissolve at least 1/10 of a solvent
B, advantageously at least 1/3, by weight and this even in the presence of the catalyst with its coordinating agents.

 Advantageously, the third solvent is added in an amount sufficient so that the amount of substrate soluble in the aqueous phase is at least of the same order of magnitude as the amount of catalyst present in the aqueous phase at the beginning of the reaction.

 Among the solvents which can be used as a third solvent, mention may be made of water-soluble solvents of the alcohol, nitrile, ether (especially cyclic), acid, sulphone, sulphoxide, single or polyfunctional amide (such as urea), ester, ketone or even amine groups in particular. in the case where said nucleophilic compound also serves as a third solvent.

 According to the invention the concept of aqueous phase must be taken in the broad sense, in fact it is not necessary that, besides the third solvent, the catalytic system and the constituents specified in the body of the present description, there is a significant proportion of water, we can obtain good results even with amounts of water as low as 5% by volume, or even less than 1%.

Some excellent results are obtained without a specific addition of water,
The water present in the undried solvents having proved sufficient.

 More precisely, rather than speaking of the aqueous phase in the sense of the term, it would be more appropriate to refer to a hydrophilic phase having hydrolyzed dissolution and solvation properties (that is, which resembles water).

 Thus it will not depart from the present invention using hydrophilic phases (that is to say having as main constituent a solvent, or a mixture of solvent, miscible in any proportion and itself miscible in large proportions ) having the property of dissolving a catalytic system of the type specified above water-soluble (that is to say water-soluble sensu stricto in all or part of the concentration range provided for in the present invention).

 As has been seen with regard to phenol, it is also possible to choose the solvent A so that it also plays the role of a third solvent B (or vice versa). In this case, solvents having a polar function of the type of that of the third solvents and having a lipophilic chain chosen so that the water dissolves said third solvent in a proportion of about 1/100 to 1/10 by weight are used.

 The metals giving the best catalytic results are the platinum group metals, preferably those which are isoelectronic palladium and the valence state which is isoelectronic palladium zero; however, it may be economically attractive to use less heavy metals because of their much lower cost; within the platinum group metals family, each of them has specificities that make them more or less interesting depending on the case; palladium, especially in the zero oxidation state, usually gives the best results.

Advantageously, said coordinating agents are trivalent hydrocarbon derivatives of the elements of column VB, advantageously of a period of a rank greater than the second and generally less than one sixth, of the periodic table of the elements (supplement to the Bulletin of the Company
Chemical of France January 1966 N 1). In addition to those which are detailed below, examples of such compounds include the derivatives of trivalent (phosphorous, arsenious, antimonious and nitrous) derived trivalent oxygen acids obtained in particular by esterification or by substitution of at most two of the three oxhydryls ( trisubstitution actually leads to pnictines which is the subject of a more detailed description).

 Among the hydrocarbon derivatives of the elements of column V, the preferred ones are those derived from hydrogen pnictures by total or partial substitution of hydrogen by hydrocarbon residues which can be connected to the VB atom by a double atom. (as in imines) or a triple bond (as in nitriles).

However, the hydrocarbon derivatives of the elements of column V advantageously derive hydrogen pnictures by total or partial substitution
hydrogen by monovalent hydrocarbon residues, advantageously by alkyls [in the present description ALco-yl is taken in its etymological sense of a hydrocarbon residue of an ALCO-ol after ignorance of the alcohol (or ol) function]; these alkylated compounds will be, by analogy with the term of pnicture, designated in the present description, under the term pnictines ..

 Thus, in the case of nitrogen, the substitution of hydrogen nitride (ammonia) gives amines, in the case of phosphorus the substitution of phosphine gives phosphines, in the case of arsenic the substitution of Hydrogen arsenide gives arsines and in the case of antimony the substitution of the antimonide (or stibide) of hydrogen gives the stibines. They are advantageously chosen from hydrocarbon derivatives of phosphorus such as phosphines.

 Advantageously, said catalyst comprises, as water-soluble coordination agent, a pnictine, a trialkylphosphine, preferably (for economic reasons) a triarylphosphine, in general a triphenylphosphine.

Said phosphine and said metal of column VIII are advantageously in the form of metal tetrakis phosphine.

 To make soluble the coordinating agents and in particular pnictines, it is appropriate to graft polar water-solubilising groups.

 Neutral groups such as polyols can be grafted, but in view of the strong lipophilicity of the pnictines, it is preferable that the grafted groups are ionic, cationic, such as quaternary or anionic ammonium, as any group constituting the associated base of the preferred acids. strong.

In the latter case, mention may be made of sulfonic, phosphonic, and more generally those giving an equivalent hydrophilicity.

 Mention may in particular be made of the groups used to modify the phosphines to obtain those referred to in the French patent filed under No. 76/22824 and published under No. 2,366,237 or in the French patent published under No. 2,549,840.

 As a paradigm of water-soluble phosphines, there may be mentioned soluble triphenylphosphinetrisulfonates P (C6H4-SO3) 3, for example alkaline and those of formula P (C6H4-CO2K) 3, preferably in anionic form.

 Thus, according to a particularly advantageous embodiment of the present invention, it is possible to use a biphasic system in which one of the two liquid phases is an aqueous phase, in which the metal of column VIII is solubilized in the aqueous phase by a pnictine, or the like , water soluble.

When there is a risk of catalyst poisoning, that is to say when using so-called "soft" nucleophiles, in general whose nucleophilic function is based on metalloids of high rank at least equal to that of phosphorus or sulfur, it is better to use:
either phosphines whose basicity is high (the basicity which is weak with triarylphosphines, increases with the number of aryl replacements by chains whose possible unsaturations [their presence is not desirable] are not conjugated with the doublets of the element of column V), such as, for example, bi- or tri-cyclohexylphosphines;
or polyfunctional pnictines, generally bifunctional, allowing chelation of the metal by pnictine functions; in general, the pnictine functions are, by taking the most direct path, separated by 2, 3, or 4 atoms, most often carbon; formulas of the type o), o-diphenylphosphinoethane; or X, (o-diphenyl phosphinobutane.

 This technique greatly facilitates the recovery and recycling of the catalyst, which recycling is one of the key parameters of the profitability of this type of process because of the ever-increasing price of the metals of the platinum mine.

In the context of the present invention, it is possible to use a metal catalyst in elemental form (zero degree of oxidation) or in oxidized form. These catalysts can be in the form of salts, oxides or complexes. Among the salts, oxides and complexes of the metals mentioned above, in the oxidation state II, mention may be made of palladium chlorides,
Palladium acetate, palladium chloride complexed with benzonitrile. It should be emphasized that anions are of minor importance, only cations count.

 Among the complexes of metals in the zero oxidation state, mention may be made of palladium dibenzylideneacetone.

 It should be emphasized that the level of oxidation of the metal is not necessarily conserved in the reactor in fact the pnictines are generally quite reducing to reduce the palladium to the elemental state even introduced palladium form.

 For a better implementation of the invention, it is preferred to use a quantity of catalyst such as the molar ratio between the metal catalyst and the compounds of the elements of column V, when the latter compounds are in the form of coordinating agents. too often referred to as the Anglo-Saxon Ligand, between 2 and 100, more generally from 4 to 30. These molar ratios must take into account the number of coordinating functions per molecule; thus when using as coordinating agent molecules having two pnictine functions, the values of the above domains should be halved.

 The amount of aqueous phase used is such that the concentration of the metal of column VIII is preferably greater than 10-5, preferably 10-210 M in the solvent.

The said nucleophilic compound must have two characteristics; On the one hand, it must be nucleophilic, that is to say, rich in electrons. On the other hand, it must be water-soluble.
In the present application, preference will be given to those which on several scales of nucleophilies have a greater than that of ammonia (see March 3rd edition pp 307 309)
In fact the choice of the nucleophile depends on the functions to be deprotected in general, it is preferred to use as nucleophiles, molecules carrying at least as nucleophilic function as the functions to which it is appropriate to be selective.

When the reagents lend themselves to it, according to a particularly advantageous embodiment of the present invention, the functions whose alkylation is to be avoided are protonated and a nucleophile which is not protonable is chosen under the operating conditions. In this hypothesis, the above constraint on the nucleophilic character becomes that the nucleophilicity must be greater than that of the NH4 + ion. This protonation is done in the aqueous phase by means of acid whose pKa is at least 1 point lower than preferably at least 2 points to the pKa of the acid associated with the nucleophilic function that it is desired to protect. An excess of at least 10% over the amount required for neutralization is preferable
These nucleophiles may be anions or neutral molecules. To illustrate the richness of this category of substrate, mention may be made in a non-limiting way:
- aliphatic organic sulphides and disulfides (primary, secondary or tertiary), aromatic or heterocyclic,
thiols,
- the pnictines (phosphines, amines ...) preferably secondary
To be hydrophilic, or rather water-soluble, that is to say it is soluble in water, said nucleophilic compound must be such that under normal conditions the water is capable of dissolving at least 0, 2, advantageously 0 Preferably 1 gram equivalent of nucleophilic function.

 It should be noted that water-soluble nucleophilic reagents can be made water-soluble or little provided with a strongly hydrophilic function on the molecule. the strong or average acid functions (pKa at most equal to 6, advantageously to 5, preferably to 4), whether sulphured, (sulphonic acid, sulfuric monoester, ....), phosphorus (phosphoric ester, phosphonic acid, phosphinic acid), carbonaceous, or other, give results good enough that one wonders if there is no synergy.

The best results are so far obtained with a carbon function namely the carboxylic function.

Thus, advantageously, the results obtained from nucleophiles where the nucleophilic function is carried by a post -vicinal carbon or preferably vicinal of that bearing the acid function. One of the best nucleophiles is
Thiosalicylic acid (HS <) -COOH), especially in monoanionic or advantageously acidic form.

It is, of course, preferable that the water and the nucleophile be miscible in any proportion. the same compound may carry several nucleophilic functions
It is preferable that there is, in relation to the number of carbon, at least one nucleophilic function per 10 carbon atoms, advantageously one for 8, preferably one for 4.

 It is also preferable to use small molecules whose carbon number is not significantly greater than the dozen.

 Finally, it may be convenient to choose a nucleophilic compound which solubility decreases considerably with the temperature to go into the gas phase thus allowing easy movement by distillation.

 In general, said nucleophilic compound is present (initially but more preferably at the end of the reaction) at a concentration of at least 1/2, advantageously 2, preferably 5 equivalent grams per liter.

 When the nucleophilic compound is reduced to a nucleophilic function, a low molecular weight of concentrations as high as 10 equivalents per gram is often exceeded.

 When the selectivity provided by the use of the aqueous phase is not considered sufficient and it is desired to increase it, it is possible to play on the excess of said nucleophilic compound with respect to the substrate, for example by increasing the stoichiometric excess (generally much greater than 10%) relative to the desired reaction to bring it to a value at least equal to 1/4, advantageously to 1/2, preferably one time, the stoichiometric amount (c ' ie working with quantities of at least 5/4, 3/2 and 2 QS, respectively).

 Thus, advantageously according to the present invention, the amount of said nucleophile is at least equal to 3/2 times the amount stoichiometrically necessary.

 Another object of the present invention is to provide a method which substantially accelerates the kinetics of cleavage.

 Another object of the present invention is to provide a process which avoids alkylation reactions of aromatic rings.

 Another object of the present invention is to provide a method which avoids the alkylation reactions of the functions described as nucleophilic.

These and other objects, which will become apparent thereafter, are achieved by a method of treating a molecule having at least one unsaturated alkyloxycarbonyl functional group where said molecule is subjected to the reagents specified above.
Advantageously, said molecules comprising at least one alkyloxycarbonyl function correspond to the following formula (I) :: ZOC (R 1) (R 2) -C (R 3) = C (R 4) (R 5) (III)
or
R1 represents a hydrogen or an alkyl radical, preferably 1 or 2 carbon atoms;
R2 represents a hydrogen or an alkyl radical, preferably with 1 or 2 carbon atoms;
R3 represents hydrogen or an alkyl radical, preferably 1 or 2 carbon atoms, or with R4 forms an additional double bond;
R4 represents hydrogen or an alkyl radical, preferably 1 or 2 carbon atoms or, with R3 forms an additional double bond;
R5 represents a hydrogen or an alkyl radical, preferably 1 or 2 carbon atoms or aryl;
Z an acyl radical including carbamyl alkoxycarbonyl thioalkoxycarbonyl and equivalent
Z contains the protected molecule and must be released from its protecting group.

R5 can be a group called "Ar" as described in the British patent application filed on 31.12.1990 under N 90 28208.8 and entitled "group
Protective"
R5 and R4 may be fractions of the so-called "Ar" group in the above application so that R5 and R4 together with the carbon bearing them form a radical ar as defined in the above British application.

R5 may be any lipophilic group as described in the French patent applications in the name of the applicant filed on 02.10.1989 under the number N 89/13054 and entitled "Peptide solubilization process and peptide synthesis process." and that deposited on 04.12.1989 under No. 89/15957 entitled "Reaction and solubilizing medium of peptides and synthetic method using this medium."
In general, the combination of the group designated by Ar in the above British application with an allyloxy carbonyl group as ULR is very favorable.

 Most often Z is of formula Z'-CO- with Z 'being the radical derived from the molecule to protect the bond replacing a hydrogen of the function whose protection is desired.

 Z has, in general, a carbon number greater than 3, most often 5, and frequently 10.

 The protected molecules are, or present as links, often amino acids and peptides, sugars and especially nucleotides.

Z 'is in general polyfunctional (in general at least bi-, more generally at least trifunctional)
It is preferable that Z 'be of structure Z "-X- with X being a non-carbon atom, advantageously V or VI columns.

 The term alkyl is taken in its previously specified etymological sense with the additional precision that it can also mean an aryl group.

 It is preferable that at least 2, advantageously 3, preferably 4, of the radicals R 1 to R 5 are at most two carbons; however, at least one of the radicals R1 to R5 may be such that the allylic alcohol is a heavy alcohol, for example an aromatic series, a terpene type or a steroidal series.

 Thus, at least 1 radical and at most 3 radicals R1 to R5 may be polycyclic aryl radicals, condensed or not, homo or heterocyclic.

 according to a most surprising aspect, the present invention makes it possible to selectively release the functions protected by allyloxycarbonyls whose substituents R1 to R5 are different: the less the allylic group is substituted, the easier the release is. More precisely, the reactivity of the different allyl groups strongly depends on the degree of substitution of the allyl group. If the number of substituents R.sub.1 to R.sub.5 is designated by p, the higher the sensitivity of p-palladium-based reagents or other metals of the Vlil column, which is isoelectronic, decreases.

 A monophasic medium distinguishes slightly less unsubstituted monosubstituted but easily distinguishes disubstituted mono.

 Finally, everything happens as if there were thresholds of effectiveness of the lower limit concentration of the different catalyst depending on the degree of substitution of the allyl group, it is thus possible to achieve extremely selective release.

 This differential reactivity between the different allyls can lead to total selectivities by modifying the parameters already mentioned: thus a biphasic medium strongly favors the little or unsubstituted allyls.

 This remarkable property allows the synthesis of complex molecules such as peptides and (poly) nucleotides by protecting with allyloxycarbonyl; functions, similar or different, whose release must be staged.

Thus the present invention makes it possible to use structural molecules: C (-CO-O-Allyl),
4 being the rest of the polyfunctional molecule
with i taking all integer values from 1 to n (n being an integer at least equal to 21, preferably 3)
allyl being of formula
-C (R1) (R2) -C (R3) == C (R4) (R5)
The allyl is advantageously such that there is in the molecule at least two, preferably 3, different formulas of allyl. It is preferable that these formulas have respectively 0, 1 and / or 2 substituents R1 to R5.

 The reaction temperature is generally between the melting point and the beginning boiling point of the reaction medium.

advantageously between 0 ° C. and 100 ° C., preferably between ambient (approximately 20 ° C.) and 50 ° C.

 It appears that the selectivity increases when the reaction is carried out in two phases but the kinetics, although generally remaining high, decrease.

 The method according to the invention respects the geometry of the molecules and is therefore particularly well suited to the chemistry of chiral molecules.

 The following nonlimiting examples illustrate the invention.

Definitions
TT = Transformation Rate:
TT = number of moles of processed product
number of moles of initial product
RR = the yield on the initial product
RR = number of moles of final product
number of moles of initial product
RT = the yield on the processed product
RT = number of moles of final product
number of moles of processed product
EXAMPLES
PRIMARY OR SECONDARY AMINE PROTECTIONS
In a flask, under argon, the amine (1 eq) is dissolved in anhydrous THF (10 ml per 1 g). The mixture is brought to 0 ° C. and then the allyl chloroformate (0.5 eq) is added dropwise for 5 minutes. After 45 minutes the mixture is brought to room temperature, the reaction is monitored by TLC (thin layer chromatography).

 After 12 hours, the precipitate is filtered with ether on celite. The organic phase is washed 3 times with 20 ml H2O (NaHCO3 / 5% HCl / H2O). The ethereal solution is dried over MgSO4 and then condensed under reduced pressure. The protected products are chromatographed on silica gel or distilled.

PROTECTIONS OF ACIDS
In a flask, under argon, is introduced the acid (1 eq) in acetonitrile, the
THF or CH2C12 anydre (10 ml for zig). The mixture is brought to oec. The DBU (1.2 eq) then the brominated derivative (1.2 eq) or the allyl chloroformate (1.2 eq) are then added. After 30 minutes, the reaction medium is brought to room temperature.

 The reaction is generally rapid, of the order of a few hours; it is followed by TLC. The reaction medium is evaporated under reduced pressure. The residue is taken up with water and extracted with 3 × 35 ml of ethyl acetate. The combined organic fractions are dried over MgSO 4 and then evaporated under reduced pressure to give yellow oils. The products are purified by chromatography on silica gel or distilled.

PROTECTIONS OF ALCOHOLS
In a flask, under argon, are introduced 1 eq alcohol and THF anydre (10 ml for 1 g). The mixture is brought to 0 ° C. and 3 equivalents of pyridine are added followed by 1.5 to 3 eq of allyl chloroformate (dropwise). After 30 minutes, the reaction medium is brought to room temperature, the reaction is monitored by TLC. After 12 hours, the reaction medium is evaporated under reduced pressure. The residue is taken up in water and extracted with ether (3 × 30 ml) or ethyl acetate (3 × 30 ml). The organic fractions are combined and dried over MgSO 4 and then evaporated under reduced pressure to give yellow oils. The products are purified by chromatography on silica gel or distilled.

DEPROTECTION IN AQUEOUS ENVIRONMENT (MONO OR BIPHASIC)
General procedure:
In a tube, under argon, are introduced the product to be deprotected and the solvent (3 ml per 100 to 500 mg of reagent). The nucleophile (diethylamine 1.2 to 15 eq) is added together with water (0.3 to 0.5 ml). The catalyst system (2.5 to 5%) is then added: Pd (OAc) 2 + TPPTS (1: 2).

 The reaction medium is then stirred vigorously, paying attention to the homogeneity of the medium. After reaction (generally very rapid for 5 to 15 minutes), the reaction medium is filtered on silica gel with a mixture (AcOEt / cyclohexane, 1: 1). The filtrate is evaporated under reduced pressure and the deprotected product can be purified by chromatography on silica gel or distilled.

 For the purpose of recycling or a reaction exceeding half an hour, the solvent, water and diethylamine must be degassed.

The solvents can be: CH3CN (for a homogeneous medium): RCN,
AcOEt (for a biphasic medium).

DEPROTECTION IN A LOW AQUEOUS ENVIRONMENT
General procedure:
The catalyst is preformed by stirring for 15 minutes under argon, Pd (dba) 2 and diphenylphosphinobutane (DPPB) coordinator (1: 1) in 1 ml of THF anydre (2.5 to 5% catalyst for the reaction). A brown-red solution is then obtained.

 In a tube, under argon, are introduced the substrate to be deprotected (100 to 500 mg) and 3 ml of anhydrous THF. Then are added the nucleophile (sulfur compound) or diethylamine (degassed), and finally the preformed catalyst system.

 When the nucleophile is diethylamine, the reaction medium is filtered on silica gel (eluent: AcOEt / cyclohexane (1: 1) The filtrate is then concentrated under reduced pressure.

 When the nucleophile is mercapto-2-benzoic acid, the latter can be separated from the deprotected product by treatment with a basic solution (10% NaOH) during extraction with ethyl acetate. The organic phase is dried and concentrated. The deprotected products can be purified by chromatography on silica gel or distilled.

RECYCLING IN AQUEOUS BIPHASIC ENVIRONMENT
Imperative degassing of solvents and nucleophile.

Operating mode:
When the deprotection reaction is complete, it is then possible to recycle the catalyst by cannulating it (at least 10 times). The recycling can be described as follows between two reaction tubes: the first contains the biphasic medium: C3H7CN (where we find the deprotected product, the excess diethylamine and the nucleophile alkylated) and water (in which is present the catalytic system), the second contains only the organic phase composed of C3H7CN, the new product to be deprotected and diethylamine. Caning can be done from the first tube to the second by pushing the aqueous phase of the first reactor into the second. The recycling must be done under argon with completely degassed reagents and solvents. The aqueous phase cannulse all the more easily as it is under the organic phase.

PROCEDURE OF EXAMPLES 1 TO 30
Protected substrate ------------------------> Substrate released
In a reactor, about 250 mg [(n = 0.0012 mole of substrate protected by the "Alloc" (= allyloxycarbonyl)] function are introduced and dissolved in 3 ml of reaction medium (for example CH 3 CN). After purging and degassing with argon, the nucleophile (diethylamine) is added (2.2 eq, n = 0.0026 mol, v = 0.272 ml) with stirring and Argon.

We then add to the reaction medium:
6.2-3 g ((n = 2.76 10-5 mol) of Pd (OAc) 2;
- 8.12 10-2 g of an aqueous solution of
TriPhenylPhosphinetriSulphonate (TPPTS) sodium (solution
aqueous 32.5%; 0.505 milliequivalent of phosphine / g) - 0.2 ml of water.

The reactions are followed by gas chromatography using, as column, the one known under the names HPI methyl
Silicon-Grum whose dimensions are 5 mx 0.53 mm x 2.65 or the known one
under the name of 8E 30 capillary, usual treatment, chromatography or
crystallization.

The crude reaction product is usually treated by evaporation of the solvents
after recovery with toluene, followed by crystallization, chromatography or distillation of the crude under reduced pressure.

 The structure of the products is verified by analysis and comparison of authentic NMR, IR gas chromatography and observation of the rotation power when treating chiral molecules.

 Yield expressed as% of recovered product.

DEPROTECTION OF ALCOHOLS
Reagents = Pd (OAC) 2, TPPTS at room temperature in CH3CN / H2O

<tb><SEP> Exemp. <SEP> Substrates <SEP> Products <SEP> Time <SEP> Yield <SEP> Report
<tb><SEP> obtained <SEP> in <SEP> mn <SEP> nucleophile
<tb><SEP> substrate
<tb><SEP> 1 <SEP> Allyloxy- <SEP> Alcohol <SEP> 10 '<SEP> 90 <SEP>% <SEP> 2,2
<tb><SEP> carbonate <SEP> benzyl
<tb><SEP> of <SEP> benzyl
<tb><SEP> 2 <SEP> Allyloxy- <SEP> Cyclohexyl <SEP> 10 '<SEP> 79 <SEP>% <SEP> 2,2
<tb><SEP> carbonate <SEP> of <SEP> carbinol
<tb><SEP> cyclohexyl
<tb><SEP> methyl
<tb><SEP> 3 <SEP> Allyloxy- <SEP> Citronelol <SEP> 5 '<SEP> 94 <SEP>% <SEP> 2,2 <SEP> and <SEP> 2,5
<tb><SEP> carbonate
<tb><SEP> of <SEP> citronellyle
<tb><SEP> 4 <SEP> (tBu) (#) 2Si <SEP> (tBu) (#) 2Si <SEP><SEP> 10 '<SEP> 98 <SEP>% <SEP> 2, 5 <SEP> eq.
<Tb>

OCH2- <SEP> OCH2
<tb><SEP> * CH (OAlloc) CH <SEP> * CHOHCH2CO
<tb><SEP> 2-COOMe <SEP> O-Me
<Tb>
ALCOHOL DEPROTECTION
Reagents = Pd (OAC) 2, TPPTS at room temperature biphasic

<tb> Examples <SEP> Substrates <SEP> Products <SEP> Time <SEP> Rendem <SEP> Report
<tb><SEP> Ne <SEP> obtained <SEP> in <SEP> mn <SEP> ent <SEP> nucleophile <SEP>
<tb><SEP> substrate
<tb><SEP> solvents ~~~ <SEP>
<tb><SEP> 5 <SEP> Allyloxy- <SEP> citronelol <SEP>><SEP> 12 <SEP> h <SEP> 51 <SEP>% <SEP> 2.5 <SEP> eq.
<Tb>

<SEP> carbonate <SEP> Et2O / H2O
<tb><SEP> decitronell <SEP> the
<tb><SEP> 6 <SEP>"<SEP>"<SEP> 3:00 <SEP> 76 <SEP>% <SEP> CH2Cl2 / H2O
<tb><SEP> 5 <SEP> eq.
<Tb>

DEPROTECTION OF ACIDS
Reagents: Pd (OAC) 2, TPPTS at room temperature CH3CN / H20
(Monophasic)

Examples <SEP> Substrates <SEP> Products <SEP> Time <SEP> Rend- <SEP> Report
<tb><SEP> N <SEP> obtained <SEP> in <SEP> mn <SEP> ment <SEP> nucleophile
<tb><SEP> substrate
<tb><SEP> 7 <SEP> 2,4 <SEP> dichlorobenzoate <SEP> Acid <SEP> 2,4 <SEP> 10 '<SEP> 98 <SEP>% <SEP> 2,2 <SEP> eq
<tb><SEP> of allyl <SEP> dichloro
<tb><SEP> benzoic
<tb><SEP> 8 <SEP> 2,4 <SEP> dichlorobenzoate <SEP>"<SEP> 10 '<SEP> 95 <SEP>% <SEP> 2,2 <SEP> eq
<tb><SEP> of <SEP> cyclohexenyl
<tb><SEP> acid
<tb><SEP> 9 <SEP> phenyl <SEP> acetate <SEP> of allyl <SEP> phenylacetic acid <SEP> 15 '<SEP> 99 <SEP>% <SEP> 2,2 <SEP> and <SEP > 2.5
<Tb>
DEPROTECTION OF PRIMARY AMINES
Reagents: Pd (OAC) 2, TPPTS at room temperature CH3CN / H2O

<tb><SEP> Examples <SEP> Substrates <SEP> Products <SEP> Rend- <SEP> Report
<tb><SEP> Ne <SEP> obtained <SEP> Time <SEP> ment <SEP> nucleophile
<tb> in <SEP> mn
<tb><SEP> substrate
<tb><SEP> 10 <SEP> N-allyloxycarbonyl <SEP> Phenylalanine <SEP> 10 '<SEP> 68 <SEP> NuH <SEP> 2,2 <SEP> eq
<tb><SEP> Phenylalanine
<tb><SEP> 11 <SEP> N-allyloxycarbonyl <SEP> Benzylamine <SEP> 9 '<SEP> 72 <SEP> 2,2 <SEP> eq
<tb><SEP> benzylamine <SEP> mine <SEP>
<tb><SEP> 12 <SEP> N-allyloxycarbonyl <SEP> a <SEP>#<SEP> 5 '<SEP> 85 <SEP> 2,2 <SEP> eq.
<Tb>

<SEP>&alpha;<SEP><SEP> methylbenzyl alcohol <SEP> methylbenzylami
<tb><SEP> no <SEP>
<tb><SEP> 13 <SEP> N-allyloxycarbonyl <SEP> Iodoaniline <SEP> 10 '<SEP> 77 <SEP> 2.2 <SEP> eq.
<Tb>

<SEP> iodine <SEP> 3 <SEP> aniline
<Tb>
DEPROTECTION OF SECONDARY AMINES
Reagents: Pd (OAC) 2, TPPTS at room temperature

<tb> Examples <SEP> Substrates <SEP> Products <SEP> Time <SEP> Yield <SEP> Report <SEP> nucleo
<tb><SEP> N <SEP> obtained <SEP> in <SEP> mn <SEP> phile / substrate
<tb><SEP> 14 <SEP>NN'allyloxycarbonyl<SEP> N-methyl <SEP> 60 <SEP> 93 <SEP> 2,2 <SEP> eq.
<Tb>

<SEP> methylbenzylamine <SEP> benzylamine <SEP> AcOEt / H2O
<tb> 15 <SEP>NN'allyloxycarbonyl<SEP> N-methyl <SEP> 15 <SEP> 82 <SEP> 2.2 <SEP> and <SEP> 4
<tb><SEP> Methylbenzylamine <SEP> Benzylamine <SEP> C3H7CN / H2O
<tb><SEP> 16 <SEP> N-allyloxycarbonyl <SEP> Morpholine <SEP> 5 <SEP> 98 <SEP> 2.2 <SEP> and <SEP> 4
<tb><SEP> Morpholine <SEP> CH3CN / H2O
<tb><SEP> 17 <SEP> N-allyloxycarbonyl <SEP> Proline <SEP> 15 <SEP> 90 <SEP> 5 <SEP> eq. <SEP> Et2O / H2O
<tb><SEP> proline
<tb><SEP> 18 <SEP> N <SEP> allyloxycarbo- <SEP> N -phenyl <SEP> p <SEP> 45 <SEP> 99 <SEP> 2.5 <SEP> eq.
<Tb>

<SEP> nyl <SEP> phenylparam- <SEP> methoxy
<tb><SEP> thoxy <SEP> glycinate <SEP> of <SEP> glycinate <SEP> of
<tb><SEP> terbutyl <SEP> terbutyl
<Tb>
DEPROTECTION OF SECONDARY AMINES (continued)
Reagents: Pd (OAC) 2, TPPTS at room temperature

<tb> Examples <SEP> Substrates <SEP> Products <SEP> Time <SEP> Yield <SEP> Report <SEP> nucleo
<tb><SEP> N <SEP> obtained <SEP> in <SEP> mn <SEP> phile / substrate
<tb><SEP> 19 <SEP> NNallyloxycarbonyl <SEP> N-methyl <SEP> 5 '<SEP> 23 <SEP>% <SEP> 2.5 <SEP> eq.
<Tb>

<SEP> methylbenzylamine <SEP> benzylamine <SEP> deprotectio <SEP> CH3CN / H2O
<tb><SEP> n
<tb><SEP> 77
<tb><SEP>% alkylation <SEP>
<tb><SEP> 20 <SEP>NN'allyloxycarbonyl<SEP> N-methyl, <SEP> 5 <SEP> 75 <SEP>% <SEP> 6 <SEP> eq.
<Tb>

<SEP> methylbenzylamine <SEP> benzylam <SEP> ne <SEP> deprotectio <SEP> CH3CN / H2O
<tb><SEP> n
<tb><SEP> 25%
<tb><SEP> alkylation
<tb><SEP> 21 <SEP>NN'allyloxycarbonyl<SEP> N-methyl, <SEP> 5 '<SEP> 97 <SEP>% <SEP> 40 <SEP> eq.
<Tb>

<SEP> methylbenzylamine <SEP> benzylamine <SEP> deprotectio <SEP> CH3CN / H2O
<tb><SEP> n
<tb><SEP> 3%
<tb><SEP> alkylation
<sep> 22 <SEP> N-allyloxycarbonyl <SEP> piperidine <SEP> 5 '<SEP> 60 <SEP>% <SEP> NuH <SEP> 2.2 <SEP> eq.
<Tb>

<SEP> piperidine <SEP> deprotectio <SEP> CH3CN / H2O
<tb><SEP> n
<tb><SEP> 40%
<tb><SEP> alkylation
<sep> 23 <SEP> N-allyloxycarbonyl <SEP> piperidine <SEP>2'30<SEP> 80 <SEP>% <SEP> 6 <SEP> eq.
<Tb>

<SEP> piperidine <SEP> deprotectio <SEP> CH3CN / H2O
<tb><SEP> n
<tb><SEP> 20 <SEP>%
<tb><SEP> alk <SEP> lation <SEP>
<tb><SEP> 24 <SEP> N <SEP> N-phenyl <SEP> p <SEP> 45 '<SEP> 100 <SEP>% <SEP> 2.5 <SEP> eq.
<Tb>

<SEP> allyloxycarbonyl <SEP> methoxy <SEP> deprotectio <SEP> (Et20 / H2O)
<tb><SEP> phenylparamethoxy <SEP> glycinate <SEP> of <SEP> n
<tb><SEP> glycinate <SEP> of <SEP> terbutyl
<tb><SEP> terbutyl
<Tb>
DEPROTECTION OF SECONDARY AMINES (end)
Reagents: Pd (OAC) 2, TPPTS at room temperature Et2O / H2O

<tb> Examples <SEP> Substrates <SEP> Products <SEP> Time <SEP> Yield <SEP> Report
<tb><SEP> N <SEP> obtained <SEP> in <SEP> mn <SEP> nucleophile /
<tb><SEP> substrate
<tb><SEP> solvent <SEP>
<tb><SEP> 25 <SEP> NNallyloxycarbonyl <SEP> N-methyl <SEP> 5 '<SEP> 84 <SEP>% <SEP> 5
<tb><SEP> methylbenzylamine <SEP> benzylam <SEP> ine <SEP> deprotection <SEP> eq. <SEP> Et2O / H2O <SEP>
<tb><SEP> 16 <SEP>% <SEP>
<tb><SEP> alkylation
<tb><SEP> 26 <SEP>NN'altyloxycarbonyl<SEP> N-methyl <SEP> 20 '<SEP> 87 <SEP>% <SEP> 8
<tb><SEP> methylbenzylamine <SEP> benzylamine <SEP>. <SEP> deprotection <SEP> eq. <SEP> Et2O / H2O <SEP>
<tb><SEP> 13%
<tb><SEP> alkylation <SEP>
<tb><SEP> 27 <SEP> N-allyloxycarbonyl <SEP> Piperidine <SEP> 10 '<SEP> 86 <SEP>% <SEP> M <SEP>"<SEP> 6 <SEP> eq. <SEP>
<Tb>

<SEP> Piperidine <SEP> 14%
<tb><SEP> alkylation <SEP> Et2O / H2O
<tb><SEP> 28 <SEP>#<SEP> N-allyloxycarbonyl <SEP> Piperidine <SEP> 5 '<SEP> 67 <SEP>% <SEP> 2.5
<tb><SEP> Piperine <SEP> Deprotection
<tb><SEP> 33 <SEP>% <SEP> eq. <SEP> Et2O / H2O
<tb><SEP> alkylation
<sep> 29 <SEP> N-allyloxycarbonyl <SEP> Piperidine <SEP> 10 '<SEP> 93 <SEP>% <SEP> 15
<tb><SEP> piperidine <SEP> deprotection <SEP> eq. <SEP> Et2O1H2O <SEP>
<tb><SEP> 7 <SEP>%
<tb><SEP> alkylation
<tb><SEP> 30 <SEP> NNallyloxycarbonyl <SEP> N-methyl, <SEP> 12 '<SEP> 84 <SEP>% "<SEP>"<SEP> 5 <SEP> eq.
<Tb>

<SEP> methylbenzylamine <SEP> benzylam <SEP> ine <SEP> 16 <SEP>%
<tb><SEP> alkylation <SEP> Et2O / H2O
<Tb>
STUDY OF SELECTIVITY a) Homogeneous medium (monophasic) CH3CN / H20

<tb> Exempl <SEP> substrate <SEP> catalyst <SEP> duration <SEP> product (s) <SEP> RDT
<tb><SEP> e <SEP> N <SEP> concentration <SEP> obtained <SEP> (s)
<tb><SEP> in <SEP>% <SEP> molar <SEP> of
<tb><SEP> 31 <SEP> phenacetate <SEP> of allyl <SEP> 5 <SEP>% <SEP> 5 <SEP> mn <SEP> acid <SEP> 100 <SEP>% <SEP>
<tb><SEP> phenacetic
<tb><SEP> 32 <SEP> phenacetate <SEP> of allyl <SEP> 2 <SEP>% <SEP> 5 <SEP> mn <SEP> acid <SEP> 100 <SEP>%
<tb><SEP> phenacetic
<tb><SEP> 33 <SEP> phenacetate <SEP> allyl <SEP> 0.5 <SEP>% <SEP> 10 <SEP> acid <SEP><SEP> 100 <SEP>% <SEP>
<tb><SEP> mn <SEP> phenacetic
<tb><SEP> 34 <SEP> phenacetate <SEP> of <SEP> 5 <SEP>% <SEP> 20 <SEP> acid <SEP> 100 <SEP>%
<tb><SEP> phenv1-3, allyl <SEP> mn <SEP> phenacetic
<tb><SEP> 35 <SEP> phenacetate <SEP> of <SEP> 2.5 <SEP>% <SEP> 20 <SEP> acid <SEP> 100 <SEP>%
<tb><SEP> phenel-3, allyl <SEP> mn <SEP> phenacetic
<tb><SEP> 36 <SEP> phenacetate <SEP> of <SEP> 1 <SEP>% <SEP> 45 <SEP> acid <SEP> 100 <SEP>%
<tb><SEP> henyl-3, <SEP> allyl <SEP> mn <SEP> phenacetic
<tb><SEP> 37 <SEP> phenacetate <SEP> of <SEP> 0.5 <SEP>% <SEP> 45 <SEP> acid <SEP> 100 <SEP>%
<tb><SEP> henyl-3, <SEP> allyl <SEP> mn <SEP> phenacetic
<tb><SEP> 38 <SEP> phenacetate <SEP> of <SEP> 5 <SEP>% <SEP> 40 <SEP> acid <SEP> 100 <SEP>%
<tb><SEP> dimethyl-3,3 <SEP> allyl <SEP> mn <SEP> phenacetic
<tb><SEP> 39 <SEP> phenacetate <SEP> of <SEP> 75 <SEP> acid <SEP> 100 <SEP>%
<tb><SEP>3,3-Dimethyl-SEP> allyl <SEP> mn <SEP> phenacetic
<tb><SEP> 41 <SEP> phenacetate <SEP> of <SEP> 480 <SEP> acid <SEP> 3.7 <SEP>%
<tb><SEP>3,3-Dimethyl-SEP> allyl <SEP> min <SEP> phenacetic <SEP> (96.3 <SEP>% <SEP> remains
<tb><SEP> unchanged
<tb> b) biphasic medium CH3CN / H20

<tb> Exampl <SEP> substrate <SEP> catalyst <SEP> duration <SEP> product (s) <SEP> RDT
<tb><SEP> e <SEP> N <SEP> concentration <SEP> obtained
<tb><SEP> in <SEP>% <SEP> molar
<tb><SEP> 42 <SEP> phenacetate <SEP> allyl <SEP> 5 <SEP>% <SEP> 10 <SEP> acid <SEP> 100 <SEP>%
<tb><SEP> mn <SEP> phenacetic
<tb><SEP> 43 <SEP> phenacetate <SEP> allyl <SEP> 2.5 <SEP>% <SEP> 10 <SEP> acid <SEP> 100 <SEP>%
<tb><SEP> mn <SEP> phenacetic
<tb><SEP> 44 <SEP> phenacetate <SEP> allyl <SEP> 1 <SEP>% <SEP> 120 <SEP> acid <SEP> 85 <SEP>%
<tb><SEP> mn <SEP> phenacetic
<tb><SEP> 45 <SEP> phenacetate <SEP> allyl <SEP> 0.5 <SEP>% <SEP> 120 <SEP> acid <SEP> 27 <SEP>%
<tb><SEP> mn <SEP> phenacetic
<tb><SEP> (73 <SEP>% <SEP> remainder
<tb><SEP> unchanged
<tb><SEP> 42 <SEP> phenacetate <SEP> of <SEP> 5 <SEP>% <SEP> none <SEP> deprotection <SEP> observed <SEP> il
<tb><SEP> 3,3-dimethyl <SEP> allyl <SEP> should <SEP> possibly <SEP> a <SEP> nucleophile <SEP> more
powerful <tb><SEP>
<tb><SEP> 47 <SEP> phenacetate <SEP> of <SEP> 5% <SEP> no <SEP> deprotection <SEP> observed <SEP> il
<tb><SEP> 3,3-dimethyl <SEP> allyl <SEP> should <SEP> possibly <SEP> a <SEP> nucleophile <SEP> more
powerful <tb><SEP>
<Tb>

Claims (5)

 1. A method useful for the selective cleavage of a molecule at least one function is protected by an allyloxycarbonyl protecting group and at least one function is protected by a protective group distinct from the previous one characterized in that it consists of bring it into contact with a reagent which comprises:  a) an aqueous phase;  b) a catalyst comprising at least one element of column VIII of the Periodic Table of Elements, said element of column VIII of the Periodic Table being maintained in the aqueous phase by complexing with at least one water-soluble coordinating agent;  c) a water-soluble nucleophilic compound. 2. Method according to claim 1, characterized in that said agents  of coordination are trivalent hydrocarbon derivatives of the elements of  column VB, advantageously of period of a rank higher than the  second 3. Method according to claims 1 and 2, characterized in that said  water-soluble coordinating agent is a pnictine, advantageously a  trialkylphosphine, preferably a triarylphosphine 4. Process according to Claims 1 to 3, characterized in that the  amount of said nucleophile is at least equal to 3/2 times the amount  stoichiometrically necessary. 5. Structure Molecule: ç (-CO-O-AllvliAn  4 being the rest of the polyfunctional molecule  with i taking all integer values from 1 to n  -ailylj being of formula  -C (R1) (R2) -C (R3) = C (R4) (R5) The alivl is advantageously such that it has in the molecule at least two. preferably 3. different formulas of allyl,