WO2014108487A1

WO2014108487A1 - P-stereogenic chiral precursor of chiral ligands and use thereof

Info

Publication number: WO2014108487A1
Application number: PCT/EP2014/050353
Authority: WO
Inventors: Damien Herault; Gérard Buono; Nicolas Vanthuyne; Christian Roussel; Laurent GIORDANO; Delphine MORALEDA; David GATINEAU; Julien Leclaire; Didier NUEL
Original assignee: Universite D'aix-Marseille; Ecole Centrale De Marseille; Centre National De La Recherche Scientifique
Priority date: 2013-01-10
Filing date: 2014-01-10
Publication date: 2014-07-17

Abstract

The present invention concerns phosphinate universal P-stereogenic chiral precursors of formula (I) for chiral ligands, preparation processes thereof and their use for the preparation of optically pure or enriched chiral ligands. Claimed are formula (I) compounds as stereoisomer, preferably enantiomer: (I) RO is a tertiary alkoxy group comprising at least 5 carbon atoms, R' is chosen in the group consisting of alkyl, alkenyl, alkynyl, heteroaryl and aryl groups, Examples for one of the claimed processes is: (II) An example for the use of such phosphinates to make other P- stereogenic ligands is (Ad means adamantyl): (III).

Description

P-stereogenic chiral precursor of chiral ligands and use thereof

The present invention concerns phosphinate universal P-stereogenic chiral precursors for chiral ligands, preparation processes thereof and their use for the preparation of optically pure or enriched chiral ligands.

Background of the invention Many active molecules, such as, but not limited to, aromas and perfumes, herbicides and pesticides, and pharmaceutically active agents, are or comprise at least one active molecule under the form of a single stereoisomer, for instance an enantiomer or a diastereoisomer. The other stereoisomers of the same molecules often have no activity, and sometimes even induce undesired side-effects. Consequently, it is preferable to obtain the desired stereoisomer in absence of the other stereoisomers. The preparation processes for said stereoisomers generally involve non stereoselective preparation, generating a mixture of stereoisomers, and thus require additional steps of separation of the stereoisomers. Such strategies are not cost-effective both because of the cost of the implementation of specific separation techniques, such as chiral separation, and because the separated non-active stereoisomer(s) represent(s) a consequent loss of matter.

Green chemistry was born at the end of the twentieth century and aims at responding both environmental and economical concerns. Among the different principles of green chemistry, catalysis represents an interesting tool as it allows the reduction of both the cost in energy and the required amount of reagents. Asymmetrical catalysis allows the preparation of great amounts of high added value chiral products from reduced amounts of chiral catalysts. As examples of chemical reactions that can be asymmetrically catalyzed may be cited catalytic hydrogenation, formation of carbon-carbon bonds, such as Heck, Sonogashira, Suzuki, Kumada, Negishi, Stille or Hiyama couplings, and asymmetrical allylic substitutions. However, the access to a chiral ligand with a reasonable cost, available in great quantities, and free in terms of rights is generally so difficult that alternatives such as chiral chromatography are preferred to produce the single enantiomers.

Chiral secondary phosphine oxides are original preligands that allow the formation of numerous chiral catalysts by association with a great number of transition metals, as described for instance in Bigeault J. et al. Synlett 2008, 1071, Bigeault J. et al. Angew. Chem. Int. Ed. 2005, 44, 4753, and Bigeault J. et al. Org. Lett. 2007, 9, 3567. These preligands can for instance assemble stereo-selectively with palladium or platinum to create complexes with a specific geometry. Said complexes have an original reactivity and can for instance catalyze new cycloaddition reactions. The stereoelectronic properties of these complexes can be easily modulated by the choice of the substituents of the phosphorus atom.

US patent application US 2010/0174079 describes a process for the production of optically active secondary or tertiary phosphine oxides using menthylphosphinate. The Applicants have now discovered novel universal P-stereogenic chiral phosphinate precursors allowing a fast, stereospecific, and cost-effective access to chiral ligands, such as chiral secondary phosphine oxides.

Summary of the invention

O

I I

RO'^H

The first object of the invention is a compound of formula (I) R , wherein

RO is a tertiary alkoxy group comprising at least 5 carbon atoms, and

R' is an alkyl, alkenyl, alkynyl, heteroaryl or aryl group.

Further objects of the invention are three processes for the preparation of a compound of formula (I).

The first process comprises contacting a tertiary alcohol comprising at least 5 carbon atoms,

CI

I

preferably 1 -adamantanol, with at least one compound of formula R' CI .

The second process comprises contacting a dichloroalkoxyphosphine, preferably dichloroadamantoxyphosphme, with at least one organolithium or organomagnesium reagent. The third process comprises contacting a compound of formula RX, wherein X is a halogen atom and R is as defined above, said RX compound being preferably an adamantyl halide, in

O

I I

HO'^H

particular adamantyl bromide, with a compound of formula R , in the presence of silver oxide (Ag₂0). A further object of the invention is the use of a compound of formula (I) in the preparation of a chiral P-stereogenic ligand or preligand, such as chiral secondary phosphine oxides. Description of the figures

Figure 1 : Chiral HPLC separation of both enantiomers of adamantylhydrogenophenylphosphinate 1 (min; Lux Cellulose-2; Hexane/ethanol 1/1 ; 1 ml/min) (a) racemic mixture (b) (-)-l (c) (+)-l. The upper spectra correspond to UV detection, and the lower spectra to circular dichroism detection.

Figure 2: Chiral HPLC separation of both enantiomers of adamantylhydrogeno-o- tolylphosphinate 2 (min; Lux Amylose-2; Hexane/ethanol 1/1 ; 1 ml/min) (a) racemic mixture (b) (-)-2 (c) (+)-2. The upper spectra correspond to UV detection, and the lower spectra to circular dichroism detection.

Figure 3: Chiral HPLC separation of both enantiomers of adamantylhydrogeno-teri- butylphosphinate 3 (min; (S,S)-Whelk-01 ; Hexane/isopropanol 7/3; 1 ml/min) (a) racemic mixture (b) (-)-3 (c) (+)-3. The spectra correspond to circular dichroism detection.

Detailed description of the invention

O

I I

RO'^H

The first object of the invention is a compound of formula (I) R , or at least one stereoisomer, preferably an enantiomer, thereof. RO is a tertiary alkoxy group comprising at least 5 carbon atoms, and R' is an alkyl, alkenyl, alkynyl, heteroaryl or aryl group.

In embodiments of the invention, R comprises at least 6, at least 7, at least 8, at least 9, or at least 10, carbon atoms. R can comprise a great number of carbon atoms. In specific embodiments, R comprises a maximum of 20, 18, or 16 carbon ato a preferred

embodiment, R is chosen in the group consisting of adamantyl Ad (AdO is

2-methyl- 2-adamantyl, 1,1 -diethyl- 1 -propyl or 3-ethyl-3-pentyl (or tertioheptyl), 2,4-dimethyl-3-(l- methylethyl)-3-pentyl, cyclobutyl-a,a,dimethylmethyl (or 2-cyclobutyl-2-propyl), 2,2,3,4,4 pentamethyl-3-pentyl and cyclobutyl(diphenyl)methyl.

In a highly preferred embodiment, R is adamantyl. In an embodiment, RO is an achiral tertiary alkoxy group comprising at least 5 carbon atoms. The term "achiral" refers to the absence of chirality of the carbon atom that is directly bound to the oxygen atom of the alkoxy group. In an embodiment, R' is chosen in the group consisting of a phenyl group, a tolyl group, preferably an o-tolyl group, a teri-butyl group, a butyl group, a / (ethylcarbonyl)phenyl group, a / iodophenyl group, a cyclohexyl group, and a o-methoxyphenyl group.

In an embodiment, R' is chosen in the group consisting of a phenyl group, a tolyl group, preferably an o-tolyl group, and a teri-butyl group.

The compounds of formula (I) or at least one stereoisomer, preferably enantiomers, thereof are universal precursors for the preparation of chiral ligands and preligands, such as chiral secondary phosphine oxides. They afford high enantioselective yields in the preparation of chiral ligands and preligands, in particular secondary phosphine oxides preligands.

The compounds of formula (I) are more stable, in terms of enantiomeric structure, than the compounds wherein the tertiary alkoxy group RO is replaced with a derivative of a primary or secondary alcohol, such as the menthylphosphinate disclosed in US 2010/0174079. Without being bound to any theory, it seems that the tertiary structure of the alkoxy group avoids epimerization of the compound in basic conditions that may trigger a loss in enantiomeric excess. The steric hindrance due to the substituents of the carbon atom which is linked to the oxygen atom of the alkoxy group seems to favor enantioselectivity.

The compounds of formula (I) or at least one stereoisomer, preferably enantiomers, thereof can be synthesized in high scale.

A process for the preparation of the compounds of formula (I), or at least one stereoisomer, preferably enantiomers, thereof, is a further object of the invention.

In an embodiment, the process for the preparation of compounds of formula (I) or at least one stereoisomer, preferably enantiomers, thereof comprises contacting a tertiary alcohol comprising at least 5 carbon atoms, preferably 1 -adamantanol, with at least one compound of

CI

I

formula R' CI _? wherein R' is as defined above. The tertiary alcohol comprising at least 5 carbon atoms can be chosen for instance in the group consisting of 1 -adamantanol, 2-methyl-2- adamantanol, 1,1 -diethyl- 1-propanol or 3-ethyl-3-pentanol (or tertioheptyl), 2,4-dimethyl-3-(l- methylethyl)-3-pentanol, cyclobutyl-a,a,dimethylmethanol (or 2-cyclobutyl-2-propanol), 2,2,3,4,4 pentamethyl-3-pentanol, and cyclobutyl(diphenyl)methanol, preferably 1- adamantanol. The process may comprise one or several steps, at least one of the steps comprising contacting a tertiary alcohol comprising at least 5 carbon atoms, preferably 1 -

Cl

I

adamantanol, with at least one compound of formula R' CI . Said contacting is preferably performed in presence of a base. The base may be chosen among basic amines, for example pyridine. The contacting may be performed in any classical solvent, for instance in dichloromethane. In an embodiment, the process for the preparation of a compound of formula (I) or at least one stereoisomer, preferably an enantiomer, thereof comprises a first step consisting in contacting a tertiary alcohol comprising at least 5 carbon atoms, preferably 1-

Cl

I

adamantanol and a compound of formula R' CI _{? n} presence of a base, preferably pyridine, in an organic solvent, preferably dichloromethane, preferably at room temperature (from 18 to 25°C), and a second step consisting in contacting the mixture obtained in the first step with water, preferably at low temperature, more preferably at 0°C.

In a further embodiment, the process for the preparation of a compound of formula (I) or at least one stereoisomer, preferably an enantiomer, thereof comprises contacting a dichloroalkoxyphosphine, wherein the alkyloxy group is a tertiary alkoxy group comprising at least 5 carbon atoms, preferably dichloroadamantoxyphosphme, with at least one compound of formula R'M, wherein R' is as defined above, and M is chosen among a lithium atom and a MgX group, wherein X is a halogen atom, preferably a chlorine or a bromine atom.

In an embodiment, the compound of formula R'M is arylmagnesium bromide.

In an embodiment, the contacting is performed in an organic solvent, such as hexane, THF, or a mixture thereof.

In an embodiment, the contacting is performed at a temperature comprised between room temperature and -78°C, preferably a temperature comprised between -30°C and -78°C, in particular at a temperature around -50°C.

In an embodiment, the process for the preparation of a compound of formula (I) or at least one stereoisomer, preferably an enantiomer, thereof comprises a first step consisting in contacting a dichloroalkoxyphosphine, wherein the alkyloxy group is a tertiary alkoxy group comprising at least 5 carbon atoms, preferably dichloroadamantoxyphosphme, with at least one compound of formula R'M, in an organic solvent, preferably hexane, preferably first at a temperature around -50°C, and then at room temperature, and a second step consisting in contacting the mixture obtained in the first step with water, preferably at a temperature around 0°C.

The process may include a preliminary step consisting in synthesizing the dichloroalkoxyphosphine, preferably dichloroadamantoxyphosphine, for instance by reacting trichlorophosphine with a tertiary alcohol comprising at least 5 carbon atoms, preferably 1 -adamantanol.

In a further embodiment, the process for the preparation of a compound of formula (I) or at least one stereoisomer, preferably an enantiomer, thereof comprises contacting a compound of formula RX, wherein X is an halogen atom, preferably an adamantyl halide, in particular

O

I I

HO'^H

adamantyl bromide, with a compound of formula R , preferably in the presence of silver oxide (Ag₂0). The conditions for said contacting can be easily adapted by anyone of ordinary skill in the art, in view of the already described processes, for instance in Georgiadis D. et al. Tetrahedron 1999, 14635.

The processes for the preparation of a compound of formula (I) or at least one stereoisomer, preferably an enantiomer, thereof of the invention may further comprise a step comprising or consisting in isolating one or more stereoisomers of the compound of formula (I). The separation can be performed for instance by chemical resolution or by chiral chromatography, in particular chiral HPLC. Among appropriate chiral HPLC columns may be cited for instance a Lux^® cellulose-2 column (Cellulose tris(3-chloro-4-methylphenylcarbamate), sold by the company Phenomenex), a Lux^® Amylose-2 column (Amylose tris(5-chloro-2- methylphenylcarbamate), sold by the company Phenomenex), a ChiralPak^® AD-H column (Amylose tris (3,5-dimethylphenylcarbamate) coated on 5 μιη silica-gel, sold by the company Chiral Technologies), a ChiralPak^® AS-H column (Amylose tris [(S)-a-methylbenzylcarbamate] coated on 5 μιη silica-gel, sold by the company Chiral Technologies), and a (S,S)-Whelk^®-01 column (sold by the company Regis Technologies).

When RO is achiral, the compounds of formula (I) as defined above with a different chirality of the phosphorus atom are enantiomers, and not diastereoisomers, and can thus not be separated by resolution. In this case, the step of isolation of one or more enantiomers of the process of the invention can be surprisingly efficiently performed by chiral chromatography. The step of isolation of one or more stereoisomers affords the possibility to obtain at least one stereoisomer of the compound of formula (I) in high scale, preferably in the gram scale, in particular in more than one gram, preferably more than two grams, highly preferably more than five grams, in 10 hours.

For instance, the enantiomers of the compound of formula (I) wherein R is adamantyl, could be separated efficiently by semipreparative chiral HPLC on a Lux^® cellulose-2 column, using methanol as eluent. The resolution factor in this case was superior at six (analytical separation on Sepapak^®-2 HR column (Sepaserve GmbH, EtOH, lmL/min). The separation of 24 g of racemic mixture easily afforded 12 g of each enantiomer.

The preparation of compounds of formula (I) according to the invention can be implemented easily and easily affords the preparation of pure compounds of formula (I). For instance, the preparation of compounds of formula (I) according to the invention does not require the use of several purification steps, in particular when RO is an achiral tertiary group. Conversely, the synthesis of the phosphinate comprising a menthyl substituent described in US2010/0174079 requires several recrystallization steps to be pure.

The compounds of formula (I), or at least one stereoisomer, preferably an enantiomer, thereof, are useful as precursors of chiral P-stereogenic ligands and/or preligands.

A further object of the invention is a process for the preparation of a chiral P-stereogenic ligand or preligand, comprising the use of a compound of formula (I) or at least one stereoisomer, preferably an enantiomer, thereof. The process for the preparation of a chiral P-stereogenic ligand or preligand can comprise a step of contacting a compound of formula (I) or at least one stereoisomer, preferably an enantiomer, thereof, with an organolithium or organomagnesium compound, in an organic solvent, preferably tetrahydrofuran, preferably at a low temperature, more preferably between -40°C and -78°C (inclusive). The chiral P-stereogenic ligand or preligand obtained by the process of the invention is also in the scope of the invention.

Preferably, the chiral P-stereogenic ligand or preligand is chosen in the group consisting of

O OH

I I I

R" ^H R"^^BH₃

compounds of formula R (secondary phosphine oxide), (borane phosphine

H

I

R""^BH₃

acid) or R (borane secondary phosphine), wherein R' is as defined above, and R' ' has the same definition as R', and may be different or identical to R'. In particular, the chiral P-stereogenic ligand or preligand is a secondary phosphine oxide. The process of the invention allows the preparation of a wide range of enantiopure or enantiomerically enriched, chemically and enantiomerically stable, alkyl and aryl phosphine oxides, borane phosphine acids and/or borane secondary phosphines, in high scale. Said ligands are important "chirons" for use in the preparation of chiral phosphorus compounds.

The synthesis of chiral secondary phosphine oxide by using a precursor according to the invention afforded yields superior or equal to 90%. Comparative tests showed that replacing the tertiary alkoxy group with a secondary alkoxy group, menthylate, caused a drastic decrease of the yields (from a yield of at least 90%> to a yield of 30 to 71%).

Another object of the invention is the use of a compound of formula (I) or at least one stereoisomer, preferably an enantiomer, thereof as starting material and/or reagent in the preparation of at least one chiral P-stereogenic ligand or preligand. Definitions

The meaning of the terms used in the present invention is generally compliant with the meaning currently admitted in the art. According to the invention, the term "alkyl" designates a saturated hydrocarbon group, linear, branched or cyclic, having from 1 to 20 carbon atoms. In an embodiment, the alkyl group has from 1 to 10, preferably from 1 to 6, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, teri-butyl, pentyl, neopentyl, n-hexyl or cyclohexyl. Methyl, teri-butyl and cyclohexyl are preferred. In another embodiment, the cyclic alkyl group comprises one, two three, four or more, in particular three or four, cycles. In particular, the cyclic alkyl group is adamantyl.

The term "alkenyl" designates a hydrocarbon group, linear, branched or cyclic, having from 2 to 20, preferably from 2 to 10, in particular from 2 to 6, carbon atoms, comprising at least one carbon-carbon double bond, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, or cyclohexenyl.

The term "alkynyl" designates a hydrocarbon group, linear, branched or cyclic, having from 2 to 20, preferably from 2 to 10, in particular from 2 to 6, carbon atoms, comprising at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, pentynyl or hexynyl. The carbon chains of the alkyl, alkenyl and/or alkynyl groups of the present invention may be interrupted by at least one, preferably 1, 2 or 3, heteroatoms chosen preferably among oxygen, nitrogen and sulphur atoms.

The term "aryl" designates a hydrocarbonated aromatic cyclic system having between 5 and 12 carbon atoms, and preferably 6 carbon atoms. One can cite, for example, the phenyl group. The aryl group can possibly have one or more substituents, chosen preferably from a halogen atom, an alkyl group, an alkoxy group or an ester group of formula COOA, wherein A is an alkyl group. The substituents may be chosen in particular from a halogen atom and an alkyl group. One can cite for example the o-, m- and / tolyl groups, in particular the o-tolyl group.

The term "heteroaryl" designates an aromatic cyclic system having between 5 and 12 atoms, comprising at least one heteroatom, preferably chosen among oxygen, nitrogen, sulphur and phosphorous atoms. In specific embodiments, the heteroaryl comprises 1, 2, 3, 4, 5, or 6 heteroatoms. One can cite for example imidazole, pyrrole, thiophene, thiazole, pyridine and furane.

The term "alkoxy" designates an alkyl, alkenyl or alkynyl group as defined above, bound to the rest of the molecule via an ether -O- bond. An alkoxy group is said to be tertiary when the carbon atom which is directly bonded to the oxygen atom of the ether bond is further linked to 3 substituents that are not hydrogen atoms.

According to the present invention, the alkoxy, alkyl, alkenyl, alkynyl, heteroaryl and aryl groups may be independently substituted with at least one group selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, heteroaryl, aryl, hydroxyl OH, ester, ether, thioether, cyano C≡N, halogen, imine, amide, amidine, and nitro NO₂ groups. In specific embodiments of the invention, the alkoxy, alkyl alkenyl, alkynyl, heteroaryl and/or aryl groups are independently non substituted.

The term "halogen" designates a chlorine atom, a bromine atom, an iodine atom or a fluorine atom. Chlorine and bromine atoms are particularly preferred.

A ligand is an ion or a molecule that binds to a central metal atom to form a coordination complex. A preligand is a chemical entity susceptible to be easily converted to a ligand. The term "P-stereogenic" designates a compound comprising at least one phosphorus atom, and wherein permutation of two substituents of the phosphorus atom triggers two stereoisomers (enantiomers or diastereoisomers).

"Stereoisomers" are isomers that have their atoms connected in the same sequence but differ in the way the atoms are oriented in space. Stereoisomers can be for instance enantiomers or diastereoisomers. The enantiomeric excess (ee) is a measure of the enantiomeric purity of a chiral compound. It is

ft — ft

defined (in percents) by the following formula: — - x lOO , wherein ni is the number of moles of the desired enantiomer, and n₂ is the number of moles of the other enantiomer.

Chemical yields are expressed in terms of molar yields in the present invention, unless specified otherwise.

The term "around" designates an interval from -10% to + 10% of the given value. The term "room temperature" designates a range from 18°C to 25°C.

Examples

Example la: Synthesis of adamantyl hydrogenophosphinates from dichlorophosphines and adamantanol

Adamantyl hydrogenophosphinates of formula (I) wherein R' is a phenyl group, an o-tolyl group or a teri-butyl group, were synthesized from the corresponding dichlorophosphines (phenyldichlorophosphine, o-tolyldichlorophosphine and teri-butyldichlorophosphine, respectively) according to the following experimental conditions and scheme with molar yields of 93%, 90% and 24%, respectively.

A solution of adamantanol (8.5 g, 56 mmol) and pyridine (4.5 mL, 56 mmol) in dichloromethane (100 mL) was added dropwise at 0°C to dichlorophenylphosphme (lOg, 56 mmol) in dichloromethane (20 mL). After 15h at room temperature, water (40 mL) was added slowly at 0°C. The two layers were separated and the aqueous phase was extracted with hexane (3 x 20 mL). The organic layers were collected and concentrated under reduced pressure. Hexane (100 mL) was added to the resulting crude and the organic phase was washed with aqueous sodium bicarbonate solution 10% (100 mL). The aqueous phase was extracted with hexane (3 x 30 mL). The organic layers were collected, dried over MgSO i, filtrated, and concentrated under reduced pressure to give adamantylhydrogenophenylphosphinate 1 (14.45 g 93 % yield).

A solution of adamantanol (898 mg, 5.9 mmol) and pyridine (0.5 mL, 5.9 mmol) in dichloromethane (10 mL) was added dropwise at 0°C to dichloro-o-tolylphosphine (1.136 g, 5.9 mmol) in dichloromethane (2 mL). After 15h at room temperature, water (2 mL) was added slowly at 0°C. The two layers were separated and the aqueous phase was extracted with hexane (3 x 5 mL). The organic layers were collected and concentrated under reduced pressure. Hexane (5 mL) was added to the resulting crude and the organic phase was washed with aqueous sodium bicarbonate solution 10%> (5 mL). The aqueous phase was extracted with hexane (3 x 5 mL). The organic layers were collected, dried over MgSO i, filtrated, and concentrated under reduced pressure to give adamantylhydrogeno-o-tolylphosphinate 2 (1.54 g, 90 % yield). A solution of adamantanol (2.94 g, 18 mmol) and pyridine (1.95 mL, 18 mmol) in dichloromethane (50 mL) was added dropwise at 0°C to dichloro(tert-butyl)phosphine (3g, 18 mmol) in dichloromethane (10 mL). After 15h at room temperature, water (10 mL) was added slowly at 0°C. The two layers were separated and the aqueous phase was extracted with cyclohexane (3 x 10 mL). The organic layers were collected and concentrated under reduced pressure. Cyclohexane (50 mL) was added to the resulting crude and the organic phase was washed with aqueous sodium bicarbonate solution 10%> (5 x 50 mL). The aqueous phase was extracted with cyclohexane (2 x 10 mL). The organic layers were collected, dried over MgSO i, filtrated, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (gradient from pure petroleum ether to pure ethyl acetate over 30 min). The desired compound adamantylhydrogeno(tert-butyl)phosphinate 3 was obtained with 24% of yield (1.17 g).

Adamantylhydrogenophenylphosphinate

White solid : ³¹P NMR (81 MHz, CDC1₃) : δ 15.2 (s); ^lH NMR (200 MHz, CDC1₃): δ 1.65 (bs, 6H), 2.13 (bs, 6H), 2.21 (bs, 3H), 7.44-7.56 (m, 3H), 7.79 (d, J = 553.3 Hz, 1H), 7.71-7.82 (m, 2H); ¹³C NMR (50 MHz, CDC1₃): δ 30.94 (3C), 35.52 (3C), 43.97 (d, J= 4.7 Hz, 3C), 82.43 (d, J = 8.5 Hz), 128.34 (d, J = 13.9 Hz, 2C), 130.67 (d, J= 11.7 Hz, 2C), 131.59 (d, J = 137.9 Hz), 132.29 (d, J = 2.8 Hz). Chiral chromatography (min; Lux Cellulose-2; Hexane/ethanol 1/1 ; 1 ml/min) : 6.30 (-), 13.11(+) (Figure 1).

Adamantylhydrogeno-o-tolylphosphinate

White solid: ³¹P NMR (121.5 MHz, CDC1₃): δ 15.24 (s). ^lB NMR (300 mHz, CDC1₃): δ 1.65- 1.67(m, 6H), 2.14-2.15 (bs, 6H), 2.22 (bs, 3H), 2.57 (s, 3H), 7.84 (d, J = 547.3 Hz, 1H), 7.21- 7.33 (m, 2H), 7.40-7.46 (m, 1H), 7.79 (ddd, J=16.1 Hz, J = 7.5 Hz, J = 1.3 Hz, 1H), 7.84 (d, J = 547.3 Hz, 1H); ¹³C NMR (100.6 MHz,CDCl₃): 31.11 (3C), 35.71 (3C), 44.03 (d, J = 4.6 Hz, 3C), 82.64 (d, J = 8.7 Hz), 125.67 (d, J = 14.4 Hz), 129.74 (d, J = 136.7 Hz), 130.94 (d, J = 12 Hz), 131.60 (d, J = 13.1 Hz), 132.34 (d, J = 2.3 Hz), 140.73 (d, J = 10.5 Hz). Chiral chromatography (min; Lux Amylose-2; Hexane/ethanol 1/1 ; 1 ml/min): 5.60 (-), 8.94 (+) (Figure 2).

Adamantylhydrogenoferfbutylphosphinate

White solid: ³¹P NMR (161 MHz, CDC1₃): δ 37.55 (s). ^lH RMN (400 MHz, CDC1₃), δ 1.06 (9H, d, J = 17.7 Hz), 1.62 (6H, m broad), 2.01 (6H, m broad), 2.17 (s broad), 6.86 (P-H, d, J=509.5 Hz); ¹³C NMR (75 MHz, CDC1₃,), δ 23,11 (3C), 30.91 (C-P, d, J=99.9 Hz), 31,23 (3C), 35.98 (3C), 44.03 (3C, d, J = 4.4 Hz), 81.6 (C-O-P, d, J = 10.5 Hz). Chiral chromatography (min; (S,S)-Whelk-01 ; Hexane/isopropanol 7/3; 1 ml/min): 7.32 (-), 10.89 (+) (Figure 3).

Example lb: Synthesis of an adamantyl hydrogenophosphinate from dichloroadamantoxyphosphine

Dichloro-(adamantoxy)phosphine

A solution of 1 -adamantanol (3.04 g, 20 mmol) in THF (15 mL) was added dropwise at -78°C to trichlorophosphine (1.75 mL, 20 mmol) in THF (15 mL). The solution was allowed to come back to room temperature and stirred overnight. Dichloro-(adamantoxy)phosphine was isolated after bulb to bulb distillation (bp 1 10°C/0.08 mbar) with 40% yield.

White solid: ³¹P NMR (162 MHz, C₆D₆): δ 191.50 (s); ^lU NMR (400 MHz, C₆D₆): δ 1.22 (bs, 6H), 1.75 (bs, 3H), 1.89 (bs, 6H).

A solution of aryl or alkyl magnesium bromide (represented below by RMgBr) (8 mmol) in THF (2 mL) was added dropwise at -50°C to dichloroadamantoxyphosphine (8 mmol) in hexane (2 mL) and the solution was allowed to come back to room temperature. After 15h at room temperature, water (2 mL) was added slowly at 0°C. The two layers were separated and the aqueous phase was extracted with hexane (3 x 5 mL). The organic layers were collected and concentrated under reduced pressure. Hexane (5 mL) was added to the resulting crude and the organic phase was washed with aqueous sodium bicarbonate solution 10% (5 mL). The aqueous phase was extracted with hexane (3 x 5 mL). The organic layers were collected, dried over MgSO i, filtrated, and concentrated under reduced pressure to give adamantylhydrogeno phosphinate (59-85 % yield).

The following compounds were obtained according to this process: adamantylhydrogenophenylphosphinate, adamantylhydrogeno-o-tolylphosphinate, adamantylhydrogenotertbutylphosphinate, adamantylhydrogeno-n-butylphosphinate, adamantylhydrogeno-cyclohexylphosphinate, adamantylhydrogeno-4- (ethyloxycarbonyl)phenylphosphinate, adamantylhydrogeno-4-iodophenylphosphinate, and adamantylhydrogeno-o-anisylphosphinate.

Adamantylhydrogeno-w-butylphosphinate

Colorless oil : ³¹P NMR (162 MHz, CDC1₃) δ 28.5 (s); ^lH NMR (400 MHz, CDC13) δ 0.85 (t, J = 7.1 Hz, 3 H), 1.35 (dq, J = 14.6, 7.1 Hz, 2 H), 1.41 - 1.53 (m, 2 H), 1.58 (t, J = 3.0 Hz, 6 H), 1.60 - 1.70 (m, 2 H), 1.96 - 2.02 (m, 6 H), 2.13 (bs, 3 H), 7.23 (d, J = 521 Hz, 1 H); ¹³C NMR (101 MHz, CDC13) δ 13.5, 23.0 (d, J = 2.2 Hz), 23.4 (d, J = 16.1 Hz), 29.1 (d, J = 97.6 Hz), 30.9 (3C), 35.6 (3C), 43.8 (d, J = 4.4 Hz, 3C), 81.2 (d, J = 8.8 Hz). Chiral chromatography (min; Whelk; Hexane/Isopropanol 70/30; 1 ml/min): 10.51 (-), 12.07 (+)

Adamantylhydrogeno-cyclohexylphosphinate

White solid : ³¹P NMR (162 MHz, CDC1₃) δ 31.9 (s); ^lH NMR (400 MHz, CDC1₃) δ 1.22 - 1.34 (m, 4 H), 1.65 (d, J = 6.3 Hz, 6 H), 1.67 - 1.74 (m, 2 H), 1.78 - 1.84 (m, 2 H), 1.85 - 1.99 (m, 2 H), 2.01 - 2.07 (m, 6 H), 2.20 (bs, 3 H), 4.02 (spt, J= 6.0 Hz, 1 H), 7.01 (dd, J= 513, 1.8 Hz, 1 H); ¹³C NMR (101 MHz, CDC1₃) δ 24.4 (d, J = 2.2 Hz), 24.6 (d, J = 1.5 Hz), 25.3, 25.8 (d, J = 2.2 Hz), 25.9 (d, J = 2.2 Hz), 31.0 (3 C), 35.8 (3 C), 37.4 (d, J = 100 Hz) 43.9 (d, J = 4.4 Hz, 3 C) 80.9 (d, J = 9.5 Hz). Chiral chromatography (min; (S,S)-Whelk-01 ; Heptane/Isopropanol 70/30; 1 ml/min): 10.48 (-), 12.15 (+)

Adamantylhydrogeno-4-(ethyloxycarbonyl)phenylphosphinate

White solid : ³¹P NMR (162 MHz, CDC1₃) δ 13.1 (s); ^lB NMR (400 MHz, CDC1₃) δ 1.40 (t, J = 7.1 Hz, 3 H), 1.65 (t, J= 3.0 Hz, 6 H), 2.12 (d, J = 3.0 Hz, 6 H), 2.21 (bs, 3 H), 4.39 (q, J = 7.3 Hz, 2 H), 7.82 (d, J= 560 Hz, 1 H), 7.84 (dd, J= 13.3, 8.0 Hz, 2 H), 8.13 (dd, J= 8.1, 2.9 Hz, 2 H); ¹³C NMR (101 MHz, CDC1₃) δ 14.2, 31.1 (3 C), 35.6 (3 C), 44.2 (d, J = 4.4 Hz, 3 C), 61.4, 83.4 (d, J = 8.8 Hz), 129.4 (d, J = 13.9 Hz, 2 C), 130.9 (d, J = 11.7 Hz, 2 C), 134.0 (d, J = 2.9 Hz), 136.3 (d J = 135.0 Hz), 165.7;. Chiral chromatography (min; Chiralpak AD-H; Hexane/Ethanol 50/50; 1 ml/min): 8.14 (+), 9.77 (-) Adamantylhydrogeno-4-iodophenylphosphinate

White solid : ³¹P NMR (162 MHz, CDC1₃) δ 13.3 (s); ^lH NMR (400 MHz, CDC1₃) δ 1.68 (t, J = 3.0 Hz, 6 H), 2.14 (d, J= 3.3 Hz, 6 H), 2.24 (bs, 3 H), 7.46 - 7.55 (m, 2 H), 7.77 (d, J= 559 Hz, 1 H), 7.85 - 7.90 (m, 2 H); ¹³C NMR (101 MHz, CDC1₃) δ 31.1 (3 C), 35.7 (3 C), 44.2 (d, J = 4.4 Hz, 3 C), 83.2 (d, J = 8.8 Hz), 100.3 (d, J = 3.7 Hz), 131.3 (d, J = 137.9 Hz), 132.3 (d, J = 11.7 Hz, 2 C), 137.8 (d, J = 13.9 Hz, 2 C). Chiral chromatography (min; Chiralpak AD-H; Hexane/Ethanol 50/50; 1 ml/min): 7.08 (-), 8.61 (+)

Adamantylhydrogeno-o-anisylphosphinate

White solid : ³¹P NMR (162 MHz, CDC1₃) δ 10.30 (s); ^lH NMR (400 MHz, CDC1₃) δ 1.58 (t, J = 3.14 Hz, 6 H), 2.04 (d, J= 3.01 Hz, 6 H), 2.13 (bs, 3 H), 3.81 (s, 3 H), 6.85 (dd, J= 8.03, 6.78 Hz, 1 H), 6.99 (td, J = 7.40, 2.51 Hz, 1 H), 7.39 (d, J = 573 Hz, 1 H), 7.41 - 7.47 (m, 1 H), 7.75 (ddd, J= 14.49, 7.47, 1.63 Hz, 1 H); ¹³C NMR (101 MHz, CDC1₃) δ 31.1 (3 C), 35.8 (3 C), 44.1 (d, J = 4.4 Hz, 3 C), 55.6, 81.9 (d, J = 8.8 Hz), 110.8 (d, J = 6.6 Hz), 119.6 (d, J = 138.6 Hz), 120.7 (d, J= 13.2 Hz), 133.1 (d, J= 6.6 Hz), 134.2 (d, J= 1.5 Hz), 161.1 (d, J= 4.4 Hz). Chiral chromatography (min; Lux-Cellulose-2, Heptane/Ethanol 50/50, 1 ml/min): 7.20 (-), 10.83 (+)

Exemple lc: Synthesis of a 3,5-dimethyladamantyl hydrogenophosphinate from l -bromo-3,5- dimethyladamantane

Phenylphosphinic acid (0.568 g, 4 mmol) and l-bromo-3,5-dimethyladamantane (2.334 g, 9.6 mmol) were dissolved in chloroform (40 ml). This reaction mixture was refluxed. Then, silver oxide (2.22 g, 9.6 mmol) was added in five equal portions, over 50 min. This solution was refluxed for an additional 1 h. After, the solvents were removed, the residue was treated with diethylether and filtered through celite. The filtrates were concentrated. The residue was purified by column chromatography using diethylether as eluent.

3,5-dimethyladamantyl hydrogenophenylphosphinate

Colorless oil : ³¹P NMR (121 MHz, CDC1₃) δ 14.4 (s); ^lH NMR (300 MHz, CDC1₃) δ 7.40 - 7.61 (m, 2 H) 7.72 - 7.84 (m, 3 H), 6.80 (d, J = 553 Hz, 1H), 2.23 - 2.10 (m, 3 H), 2.05 - 1.90 (m, 4 H), 1.45 - 1.32 (m, 4 H), 1.04 (s, 2 H), 0.91 (s, 6 H)

Example 2: Separation of adamantyl hydrogenophosphinates

The three adamantyl hydrogenophosphinates obtained according to example la were separated by chiral liquid chromatography. Figure 1 presents the HPLC separation of both enantiomers of adamantyl phenyl hydrogenophosphinate (R'=Ph) synthesized according to example la on a Lux^® cellulose-2 column (Cellulose tris(3-chloro-4-methylphenylcarbamate), sold by the company Phenomenex), with a 1 cm diameter, with methanol as solvent, at 30°C. The experimental conditions are the following:

Amount of racemic separated by injection: 1 mg

Number of injections: 700

Duration of an injection: 2.4 min

Total duration of the separation: 30 hours

Amount of solvent: 9 liters

- Weight of 1^st eluted enantiomer: 6.0 g (99% ee)

- Weight of 2^nd eluted enantiomer: 6.2 g (98% ee).

This separation affords a productivity of 2 g of each pure enantiomer of compound 1 in 10 hours, confirming the possibility for high scale production of each enantiomer.

The separation could also be performed as efficiently with a Lux^® Amylose-2 column (Amylose tris(5-chloro-2-methylphenylcarbamate), sold by the company Phenomenex).

Separation of the enantiomers of adamantyl o-tolyl hydrogenophosphinate 2 was performed efficiently with a Lux^® Amylose-2 column. Figure 2 presents the HPLC separation of both enantiomers of adamantylhydrogeno-o-tolylphosphinate 2 synthesized according to example la. Separation of the enantiomers of adamantyl tert-butyl hydrogenophosphinate 3 was performed efficiently with a ChiralPak^® AD-H column (Amylose tris (3,5-dimethylphenylcarbamate) coated on 5 μιη silica-gel, sold by the company Chiral Technologies), a ChiralPak^® AS-H column (Amylose tris [(S)-a-methylbenzylcarbamate] coated on 5 μιη silica-gel, sold by the company Chiral Technologies), and a (S,S)-Whelk^®-01 column (sold by the company Phenomenex). Figure 3 presents the HPLC separation of both enantiomers of adamantylhydrogeno-tert-butylphosphinate 3 synthesized according to example 1 a.

Example 3 : Stability study The stability of the enantiomers of each of the three phosphinates was assessed. Control by chiral HPLC (High Performance Liquid Chromatography), polarimetry, ^lH and ³¹P NMR (Nuclear Magnetic Resonance) confirmed that each enantiopure compound was chemically and configurationally stable in ambient conditions for several months. Comparatively, phenyl hydrogenophosphinates were synthesized, wherein the adamantyl group is replaced with an ethyl (primary alkoxy group) or an isopropyl (secondary alkoxy group) group. Both compounds are chemically and configurationally unstable. Example 4: Use of adamantyl hydrogenophosphinates for the synthesis of secondary phosphine oxides

Each of the enantiopure compounds obtained according to example 2 was contacted with a compound of formula R"M, wherein M is Li or MgX, to produce the corresponding secondary

O

I I

R'" »;'H

phosphine oxide preligand of formula R with good yields and high enantiospecificity. The reaction was performed in particular according to the following scheme, wherein R' is phenyl:

R"Li, THF

AdO' i 'H R"

Ph

O

R"Li, THF p.

AdO' i 'Ph R A 'Ph

H H

The table below presents the conditions and results of the reaction for R" being tert-butyl, n- butyl and 1 -naphthyl.

The following experimental procedures were followed:

R" = tert-butyl

A dry Schlenk tube was charged under argon atmosphere with a solution of tert-butyl lithium (12 mmol) in THF (12 mL) and cooled down to -78°C. A solution of adamantoxy phenyl phosphinate 1 (4 mmol) in THF (12 mL) was added dropwise, the reaction mixture was stirred at -78°C for 4h and the solution was allowed to come back to -30°C. The reaction mixture was treated with water (3 mL) then NH₄C1 saturated aqueous solution (12 mL). The reaction mixture was then diluted with Et₂0 (12 mL). The organic phase was separated off, and the aqueous phase was extracted with AcOEt (3 x 12 mL). The combined organic layers were dried over Na₂S0₄, filtered and concentrated under vacuum.

The purification of the crude by chromatography on a short plug of desactivated silica gel (20% H₂0) using a gradient of Et₂0/light petroleum 0/100 to 100/0 as eluent, afforded the expected product with 80% yield.

R"= n-butyl

A dry Schlenk tube was charged under argon atmosphere with a solution of butyl lithium (3 mmol) in THF (3 mL) and cooled down to -78°C. A solution of adamantoxy phenyl phosphinate 1 (1 mmol) in THF (3 mL) was added dropwise, the reaction mixture was stirred at -78°C for 14h and the solution was allowed to come back to -30°C. The reaction mixture was treated with water (0,8 mL) then NH₄C1 saturated aqueous solution (3 mL). The reaction mixture was then diluted with Et₂0 (3 mL). The organic phase was separated off, and the aqueous phase was extracted with AcOEt (3 x 3 mL). The combined organic layers were dried over Na₂SO (, filtered and concentrated under vacuum.

The purification of the crude by chromatography on a short plug of desactivated silica gel (20% H₂0) using a gradient of Et₂0/light petroleum 0/100 to 100/0 as eluent, afforded the expected product with 60% yield.

R"= 1-naphthyl

Preparation of the naphthyl lithium solution

In a Shlenk tube under inert atmosphere, 0.62 lg (3 mmol, 3 eq.) of 1-naphthyl bromide were dissolved in 2mL of diethyl ether and cooled to -60 °C. 3.16 mL of a 1.9M solution of ter- butyllithium in hexane (6 mmol, 6 eq.) were added dropwise. The mixture was allowed to warm to room temperature and was stirred for 1 hour at this temperature (formation of a white precipitate).The suspension was then cooled to -60°C and 3 mL of freshly distilled THF (tertahydrofuran) were slowly added.

Reaction with adamantoxy phenyl phosphinate

A solution of 0.276 (1 mmol) (S_P) - adamantoxy phenyl phosphinate 1 in 2 mL of freshly distilled THF was prepared under inert atmosphere. This solution was added dropwise to the solution of naphtyllithium at -60 °C. The mixture was stirred at this temperature for 4 hours. The resulting suspension was allowed to warm to -30 °C. 3mL of a 2% solution of hydrochloric acid were then added and the mixture was allowed to reach room temperature (if the aqueous phase was not clear, 1 mL of water could be added to obtain perfectly clear phases).

The two phases were separated and the aqueous phase was extracted 3 times with 3 mL of ethylacetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated to dryness. Purification

The compound was purified by chromatography on a deactivated silica (lg of silica gel shaken with 0.2g of water (20% w:w)) using successively 50 mL of petroleum ether, 50 mL of a mixture 1 :1 petroleum ether : diethyl oxide and 50 mL of diethyl oxide.

A 100%) conversion was found by NMR (Nuclear Magnetic Resonance), the isolated yield was 40%), and the enantiomeric excess was determined to be 98%>.

Claims

O

RO' i ^H

1. Compound of formula (I) R' , wherein

RO is a tertiary alkoxy group comprising at least 5 carbon atoms, and

R' is chosen in the group consisting of alkyl, alkenyl, alkynyl, heteroaryl and aryl groups,

or at least one stereoisomer, preferably an enantiomer, thereof,

wherein the alkoxy, alkyl, alkenyl, alkynyl, heteroaryl and aryl groups may be independently substituted with at least one group selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, heteroaryl, aryl, hydroxyl OH, ester, ether, thioether, cyano C≡N, halogen, imine, amide, amidine, and nitro NO₂ groups, and

wherein an alkyl group is a saturated hydrocarbon group, linear, branched or cyclic, having from 1 to 20 carbon atoms,

wherein an alkeny group is a hydrocarbon group, linear, branched or cyclic, having from 2 to 20 carbon atoms, comprising at least one carbon-carbon double bond, and wherein an alkynyl group is a hydrocarbon group, linear, branched or cyclic, having from 2 to 20 carbon atoms, comprising at least one carbon-carbon triple bond.

2. Compound according to claim 1, wherein R is chosen in the group consisting of adamantyl, 2-methyl-2-adamantyl, 1,1-diethy 1-1 -propyl, 2,4-dimethyl-3-(l- methylethyl)-3-pentyl, cyclobutyl-a,a,dimethylmethyl (or 2-cyclobutyl-2-propyl), 2,2,3,4,4 pentamethyl-3-pentyl, and cyclobutyl(diphenyl)methyl.

Compound according to claim 2, wherein R is adamantyl.

Compound according to claim 1 or 2, wherein RO is an achiral tertiary alkoxy group comprising at least 5 carbon atoms.

Compound according to any of claims 1 to 4, wherein R' is chosen in the group consisting of a phenyl group, a tolyl group, and a tert-butyl group.

Compound according to claim 5, wherein R' is an o-tolyl group.

Process for the preparation of a compound of formula (I), or at least one stereoisomer, preferably an enantiomer, thereof, comprising contacting a tertiary alcohol comprising CI

I

at least 5 carbon atoms, with at least one compound of the formula R' CI _? wherein formula (I) and R' are as defined in claim 1.

8. Process according to claim 7, wherein the tertiary alcohol comprising at least 5 carbon atoms is chosen in the group consisting of 1 -adamantanol, 2-methyl-2-adamantanol, 1 , 1 -diethyl- 1 -propanol, 2,4-dimethyl-3 -( 1 -methylethyl)-3 -pentanol, cyclobutyl- a,a,dimethylmethanol (or 2-cyclobutyl-2-propanol), 2,2,3,4,4 pentamethyl-3 -pentanol, and cyclobutyl(diphenyl)methanol, preferably 1 -adamantanol.

9. Process for the preparation of a compound of formula (I), or at least one stereoisomer, preferably an enantiomer, thereof, comprising contacting a dichloroalkoxyphosphine, wherein the alkyloxy group is a tertiary alkoxy group comprising at least 5 carbon atoms, with at least one compound of formula R'M, wherein R' is as defined in claim 1 , and M is chosen among a lithium atom and a MgX group, wherein X is a halogen atom.

10. Process according to claim 9, wherein the dichloroalkoxyphosphine is dichloroadamantoxyphosphine.

1 1. Process for the preparation of a compound of formula (I), or at least one stereoisomer, preferably an enantiomer, thereof, comprising contacting a compound of formula RX,

O

I I

HO'^H

wherein X is a halogen atom, with a compound of formula R , in the presence of silver oxide.

12. Process according to claim 1 1 , wherein the compound of formula RX is an adamantyl halide, preferably adamantyl bromide.

13. Process for the preparation of a compound of formula (I), or at least one stereoisomer, preferably an enantiomer, thereof, according to anyone of claims 7 to 12, further comprising a step comprising isolating one or more stereoisomers of the compound of formula (I) by chemical resolution or by chiral chromatography, in particular chiral HPLC.

14. Process for the preparation of a chiral P-stereogenic ligand or preligand, comprising the use of a compound of formula (I), or at least one stereoisomer, preferably an enantiomer, thereof, as defined in claim 1 , wherein the ligand is an ion or a molecule that binds to a central metal atom to form a coordination complex and the preligand is a chemical entity susceptible to be converted to a ligand.

15. Process according to claim 14, wherein the chiral P-stereogenic ligand or preligand is

chosen in the group consisting of compounds of formula

or

H

I

R" "^BH₃

R , wherein R' is as defined in claim 1 , and R" has the same definition as R', preferably the chiral P-stereogenic ligand or preligand is a compound of formula