FR2900406A1 - New C-glycoside compounds useful e.g. to make cosmetological-, medical imaging- and/or immunological compositions, preferably dermatological composition to protect the skin, lips, hair and scalp against oxidative and UV radiation stress - Google Patents

Abstract

C-Glycoside compounds (I) and their derivatives of base, additive salts of mineral/organic acids, hydrates or solvates, are new. C-Glycoside compounds of formula (I) and their derivatives of base, additive salts of mineral/organic acids, hydrates or solvates, are new. Y 1>H (preferred) or halo; X : H or alkyl (which is having amine, amide, acid, ester, carbonyl, alcohol or aryl group), carbonyl, ester, amide, amine or alcohol; R : OH or OR1a; R1a : alkyl, benzyl, benzoyl, acetyl, pivaloyl, trialkylsilyl, tert-butyldiphenylsilyl or sugar e.g. furanose or pyranose; R 1>OR1a, NR1bR1c, N 3 or phthlimide; R1b, R1c : H, alkyl, aryl, benzyl, benzoyl, acetyl, alkyloxycarbonyl, allyloxycarbonyl or benzyloxycarbonyl; R 2>H, halo, OH, OR1a, NR1bR1c or N 3, preferably H, OH, Br or Cl; and n : 1-2, preferably all alkyls are 1-15C alkyl. An independent claim is included for the preparation of (I). [Image].

Description

The present invention relates to a new family of sugar mimes

of C-glycosides and C-glycoconjugates type which can be used in many fields such as cosmetology, medical imaging, or even in pharmaceutical applications, for example as an antifungal, antiparasitic, anti-thrombotic, antibiotics, antiviral, anti -infectious, anti-inflammatory, antipsychotic, antidepressant or even antineoplastic.

In general, it is known that sugars constitute a fundamental class of biomolecules, involved in very varied functions: They do not only constitute forms of energy reserve, but they participate in cellular communications, in the functioning of the body. immune system, help the body to fight against pathogenic microorganisms, and intervene in the processes of cancerization. It is therefore this ability to communicate with other cells, proteins, hormones, viruses, toxins or bacteria that make sugars a real arsenal for the development of new treatments 25, in particular in the field of cancers, viruses, inflammation and many more.

They are present in known drugs such as drugs for the cardiovascular system with cardiac glycosides, anticoagulants with heparin, antibiotics of the aminoglycosides or glycopeptides, antineoplastics of the type cytotoxic antibiotics and others. In addition, the addition of water-soluble sugars to medicinal active ingredients makes it possible to improve their solubility in biological media and to modify their pharmacokinetic properties (circulation, elimination and concentration in biological media -2). . Glycosylation can also delay degradation processes (this is particularly the case with peptides such as opioid peptides: enkephalins), influence transport across many barriers such as the blood-brain barrier, and thus block entry into the brain or on the contrary facilitate its transport by targeting active glucose transport systems. In addition, glycosylation can also enhance interactions with receptors or lectins present at the surface of cells and thus induce greater vectorization and selectivity in the form of glycoconjugates.

The fact remains that, despite the therapeutic potential of glycosides and their derivatives, their commercial use for the development of new drugs is often overshadowed by major drawbacks:

high costs and difficulties of synthesis, purification and analysis, high instability in the face of chemical and enzymatic hydrolysis processes and therefore rapid degradation in the organism, in particular by the glycosidases present in large numbers in this medium.

Knowledge of the therapeutic potential of sugars and their limitations has strengthened the search for mimetics of these structures, as a new way of access to more effective therapeutic agents. And if some of them have found applications, it is always on an ad hoc basis. There is thus a large variety of hybrid structures of sugars which have been developed: among them, the Cglycosides constitute a major advance in the resolution of the problems of stability of sugars and their derivatives.

In this field, two families have emerged: CH2 and CF2-Glycosides, in which the anomeric oxygen is replaced by a CH2 or CF2 group in order to overcome the problems of stability of sugars. However, if CH2 is of great interest in terms of stability, the replacement of anomeric oxygen by this group induces significant changes in terms of electronegativity, polarity and therefore behavior of the new sugar in biological phenomena. The replacement of the anomeric oxygen by a CF2 induces good stability, but above all an excellent substitution in terms of electronegativity. However, the presence of CF2, due to the inductive attracting effect of the 2 fluorine atoms, can sensitize neighboring functions, such as carbonyls which can thus undergo attacks by nucleophilic functions such as amines.

The object of the invention is more particularly to eliminate these drawbacks by virtue of a new family of sugar mimes: C-glycosides and C-glycoconjugates in which the oxygen of the anomeric function is replaced by a group comprising a carbon atom bearing a fluorine atom, stable against enzymatic degradation and acid-base hydrolysis, and exhibiting reduced sensitivity to nucleophilic attacks.

More particularly, it provides a stabilized C-glycoside compound which, used as an analogue or adduct / vehicle of biologically active compounds, can improve their activity.

According to the invention, this C-glycoside compound has the following formula I: CFY X 20 where n is an integer equal to 1 or 2, Y represents a hydrogen atom or a bromine or chlorine atom, X is a hydrogen atom or a linear or branched alkyl chain having at least one amine, amide, acid, ester, carbonyl, alcohol, aryl or a carbonyl, ester, amide, amine, free or protected alcohol group, R identical or different , represent an OH or OR 'group where R' is a linear or branched alkyl, benzyl, benzoyl, acetyl, pivaloyl, trialkylsilyl, tert-butyldiphenylsilyl group or one or more sugars, R 'represents OR', NR "R" ', N3, or a phthalimide R "and R" ', identical or different, represent a hydrogen atom or a linear or branched alkyl, aryl, benzyl, benzoyl, acetyl, alkyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, R2 represents a hydrogen atom or a halogen, preferably a halogen chosen from F, Cl, Br, I, or an OH, OR, NR "R" 'or N3 group, as well as its derivatives in the form of a base, of addition salt with an inorganic or organic acid, of hydrate or of physiologically or pharmaceutically acceptable solvate.

The linear or branched alkyl groups may be groups having from 1 to 15 carbon atoms.

This new family of C-glycosides and of monofluorinated C-glycoconjugates advantageously makes it possible to obtain either: 1. Stabilization of glycoconjugates: the preparations of analogues modified by this technology of glycosides and glycoconjugates, will thus be able to exhibit better stability, bioavailability and therefore efficacy than the parent compounds. In addition, they can more easily be administered orally. This will improve their use as a medicine. 2. Neo-glycosylation: the preparation of glycosylated versions of active medicinal principles. The addition of water-soluble sugars to medicinal active principles makes it possible to improve their solubility in biological media and to modify their pharmacokinetic properties (circulation, elimination and concentration in biological media). Glycosylation can also delay degradation processes (this is particularly the case with peptides such as opioid peptides: enkephalins), influence transport across many barriers such as the blood-brain barrier, and thus block entry into the brain or on the contrary facilitate its transport by targeting active glucose transport systems. Glycosylation is also important for barriers such as the placental barrier and can thus prevent intoxication of the fetus. In addition, glycosylation can also enhance interactions with receptors or lectins present at the surface of cells and thus induce greater vectorization and selectivity in the form of glycoconjugates. In addition, these compounds will benefit from greater stability and the effect of the introduction of the fluorine atom.

A subject of the invention is also a process for the preparation of the compounds of formula I.

According to a first variant, said compounds of formula I in which Y represents a hydrogen molecule may be obtained by a process comprising a reaction of an alkyl dibromofluoroacete in the presence of diethylzinc and triphenylphosphine on the lactones of formula II: with n, R, RI as defined above.

Compounds of formula I in which X and Y are hydrogen atoms and R2 represents hydroxyl (OH) can be obtained as side products of the reaction of a compound of formula I in which R2 = OH, Y = H and X = CO2H in the presence of a peptide coupling agent such as 3-ethyl-1 (N, N-dimethylaminopropylcarbodiimide (EDCI) or dicyclohexyl carbodiimide (DCC) in the presence of a tertiary amine such as N-methylmorpholine ( NMM) or diisopropylethylamine (DIEA).

According to a second variant, said compounds of formula I in which Y represents a hydrogen molecule can be obtained by a process -6 comprising a Reformatsky addition reaction of an alkyl bromofluoroacetate in the presence of zinc on the lactones of formula II.

Advantageously, the choice of one or the other of these two variants makes it possible to favor one or the other of the configurations of the asymmetric center carrying the fluorine atom.

According to a third variant, said compounds of formula I in which Y represents a halogen atom such as chlorine and bromine may be obtained by a process comprising a reaction of the alkyl dihalofluoroacete in the presence of diethylzinc with the lactones of formula II.

Said lactones may be obtained by conventional steps of protection by benzylation of the sugar, followed by the acid hydrolysis of the anomeric position, then by its oxidation.

The compounds of general structure I with R2 = OH may be halogenated to obtain compounds of general structure I with R2 = Cl or Br then reduced to obtain compounds of general structure I with R2 = 1-I.

The compounds of formula III, also obtained with the preparation process using diethylzinc, dibromofluoroacetate and triphenylphosphine may constitute active compounds. with n, R, R1, X as defined above. More specifically, compounds of formula III in which X = Br can be obtained by reaction of lactone of formula II in the presence of tribromofluoromethane (CFBr3), triphenylphosphine and diethylzinc.

Compounds of formula III in which X = H can be obtained by reacting a compound of formula I in which X = CO2H, R2 = OH and Y = H is reacted in the presence of a peptide coupling agent such as 3-ethyl-1 (N, N-dimethylaminopropylcarbodiimide (EDCI) or dicyclohexyl carbodiimide (DCC) in the presence of a tertiary amine such as N-methylmorpholine (NMM) or diisopropylethylamine (DIEA).

In the compounds of general formula III, the double bond may be reduced to give compounds of general formula I with R2 = H and Y = H, but also: - compounds of formula IV where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or an OH, OR group, and obtained from the ester (X = CO2Et in formula I), or by reduction with diisobutylaluminum hydride (DIBALH ), or by reduction in alcohol (formula V) followed by oxidation - compounds of formula V 10 -8 where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or a OH group, OR Z represents an OH, OR3 with R3 = alkyl, benzyl, mesyl, tosyl, triflate or a halogen such as Cl, Br, I.

- compounds of formula VI COR "" where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or an OH group, OR Z1 represents an H or NR "R" ' where R "and R" ', identical or different, represent a hydrogen atom or a linear or branched alkyl, aryl, benzyl, benzoyl, acetyl, alkyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, R "" group represent OR "or NR" R "'or an amino acid obtained by reaction of the Wittig-Wadsworth-Horner-Emmonth type of a phosphonate on the aldehyde of formula IV

- compounds of formula VII COR "" where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or an OH group, OR Z1 represents an H or NR "R" ' with R "and R ', identical or different, represent a hydrogen atom or a linear or branched alkyl, aryl, benzyl, benzoyl, acetyl, alkyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, R' represent OR" or NR "R" 'group or an amino acid obtained by reduction of the double bond of formula VI

- compounds of formula VIII where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or an OH, OR, 20 group and obtained from the ester (X = CO2Et in formula I), by acid saponification (X = CO2H in formula I) by the action of lalithin or soda or potash, followed by peptide coupling with AA: an amino acid or a peptide is i.e. a chain of amino acids in the presence of conventional coupling agents such as dicycohexylcarbodiimide (DCC), 3-ethyl-1 (N, Ndimethylaminopropylcarbodiimide (EDCI), (2- (7-Aza-1H) benzotriazol-1-yl) -15 - 10 - 1,1,3, 3-tetramethyluronium hexafluorophosphate) (HATU), (2-1H benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (HBTU) with or without Hydroxybenzotriazole (HOBt), and a tertiary amine such as N-methylmorpholine (NMM) or diisopropylethylamine (DIEA) or triethylamine (Et3N).

- compounds of formula IX where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or an OH group, OR, R4 represents a hydrogen, halogen, NR "R" ', OH or OR "with R" and R "', identical or different, represent a hydrogen atom or a linear or branched alkyl, aryl, benzyl, benzoyl, acetyl, alkyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, or obtained from l ester (X = CO2Et in formula I), by saponification to acid (X = CO2H in formula I) by the action of alithine or soda or potash, followed by coupling with an aromatic amine in the presence of 'conventional coupling agents such as DCC, EDCI, HATU, HBTU) with or without HOBT, and of a tertiary amine such as NMM, DIEA, Et3N.

The invention also relates to a C-glycoside compound of formula I in which the radical R2 consists of an OH group present, when it is in solution in polar and protic solvents, in the various conventional forms of sugars in solution, at namely: open forms, furanosis and pyranosis. -11- Thus, for example, in the galactose series, the compound may have the following formula X: e-CF f5-CF a-CF o 0 Furanoses Linear HO - CF HO 'OH OR Pyranoses The advantage of C-glycoside compounds or C-glycoconjugates according to the invention compared to prior technologies and to natural glycosides and glycoconjugates resides in: The existence of electronegativity due to the presence of a fluorine atom makes it possible to conserve the polarity of the molecule. Its character particularly resistant to enzymatic degradation and to acid-base hydrolysis conditions therefore makes it possible to obtain non-hydrolyzable compounds (chemically and enzymatically), which will have a beneficial effect in terms of bioavailability and the shelf life of these compounds. when used as medicaments. It thus improves metabolic stability, by blocking a metabolic site with a fluorine atom, an atom small enough not to disadvantage interactions with receptors. An inductive effect due to the fluorine atom, which has no weakening effect on neighboring functions against nucleophiles. The introduction of an asymmetric center on the anomeric position, could induce a better affinity in interactions with receptors, since this position is often involved in natural glycosides in interactions with receptors. The modifications of the physicochemical properties, and in particular at the level of the acidity and of the basicity of the neighboring functions, are extremely similar in the case of the introduction of a single fluorine atom, of compounds having an oxygen. Often, changes in pKa have a very strong effect on the pharmacokinetics and interactions of a molecule. - The impact in interactions with proteins, this effect can be direct between fluorine and protein or indirect via functions similar to fluorine whose polarity is thus modified, it being understood that CF ... C = O interactions can play a role an important role in thus significantly increasing interactions. Examples of preparation of compounds according to the invention will be described below, by way of non-limiting examples, with reference to the accompanying drawings in which: FIG. 1 is a reaction equation for obtaining compound 2a12a2; 2b1 / b2; 2c1 / 2c2 Figure 2 is a reaction equation to obtain compound 2a1 / az; 2b1 / b2; 2c1 / çZ; as well as 3a1 / 3a2; 3b1 / b2; 3c1 / ç2 Figure 3 is a reaction equation to obtain compound 4a] [/ 4a2; 4b1 / 4b2; 4c1 / 4c2; Figure 4 is a reaction equation to obtain compound 5a1 / 512; 5b1. Figure 5 is a reaction equation to obtain compound 6.e; %; Figure 6 is a reaction equation to obtain compound 7a ~; 7b1 / 7b2; Figure 7 is a reaction equation to obtain compound 8b1 / b; Figure 8 is a reaction equation to obtain compound 9b1 / 9b2; Figure 9 is a reaction equation to obtain compound 10b2; Figure 10 is a reaction equation to obtain Compound IIaI 11b2; Figure 11 is a reaction equation to obtain compound 10a1; Figure 12 is a reaction equation to obtain compound 12a1. Figure 13 is a reaction equation to obtain compound 13..e; Figure 14 is a reaction equation to obtain compound 10a; Figure 15 is a reaction equation to obtain compound 14a1W42; - 13 - Figure 16 is a reaction equation to obtain compound 15a1; Figure 17 is a reaction equation to obtain compound 16a1; Figure 18 is a reaction equation to obtain compound 17a1; Figure 19 is a reaction equation to obtain compound 18b1.

Figure 20 is a reaction equation to obtain compound 19b1 / 19b2; Figure 21 is a reaction equation to obtain compound 20b1 / 20b2; Figure 22 is a reaction equation to obtain compound 21b; Figure 23 is a reaction equation to obtain compound 22a1142; 23 Figure 24 is a reaction equation to obtain compound 24b1 / 24b2 Figure 25 is an example of enzymatic degradation of 0-glycopeptides by glycosidases Figure 26 is an example of resistance of CHF-glycopeptides to glycosidases The abbreviations encountered are defined as follows:

eq. : equivalent g: gram Hz: Hertz mg: milligram MHz: megaHertz min .: minute mL: milliliter mmol: millimole mol: micromole nmol: nanomole ed: diastereomeric excess The characteristics of the devices used to perform the analyzes of all the compounds described in the present application are indicated below: The 1 H, 13C, 19F NMR spectra were recorded on BRUKER DPX 300 and DPX 600 spectrometers. In 1H and 13C NMR, tetramethylsilane is used as internal reference. In 19F NMR, the external reference is CFC13 fluorotrichloromethane. The chemical shifts are expressed in parts per million (ppm), the coupling constants J in Hertz (Hz). The following abbreviations have been used: s for singlet, bs for a large singlet, d for doublet, t for triplet, qdt for quadruplet, m for multiplet or solid, dd for doublet of doublet ... - 14 - Mass spectra were obtained on a Micromass TOFSPEC type spectrophotometer, E 20 kV, α-cyano. for Maldi and JEOL AX500 ionization, 3 kV, Canon FAB JEOL, Xe, 4 kV, limit current 10 A, Gly-NBA 50: 50 for FAB ionization.

The separations by column chromatography are carried out under light pressure following the techniques of chromatography on Kieselgel 60 silica (230-400 Mesh, Merck). Monitoring is carried out by thin layer chromatography (TLC) with Kieselgel 60E-254-0.25mm plates. The ratio of the migration distance of a compound on a given support to the migration distance of an eluent is called the frontal ratio (Rf).

Synthesis of gal / 2a ~ compounds (Figure 1)

In a flask under an inert atmosphere containing Zinc (2.55 g; 38.96 mmol; 7 eq.) Previously activated and pickled, THF (40 mL) is added. The medium is brought to reflux, then a mixture consisting of lactone 1a (3 g; 5.57 mmol; 1 eq.) And ethyl bromofluoroacetate (1.97 mL; 16.7 mmol;) is added dropwise. 3 eq.) In THF (40 mL). The reaction is left at reflux for 3 hours. After returning to ambient temperature, a 1N HCl solution (60 mL) is added to the reaction medium. The mixture is filtered through a Buchner funnel to remove excess zinc. Dichloromethane (40 mL) is added to the solution. The 2 phases are separated and the aqueous phase is extracted twice again with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated. The mixture is then purified on a silica column with as eluent a cyclohexane / ethyl acetate mixture in proportions of 8 to 2 to obtain a colorless oil for the minority diastereoisomer 2a1 and a light yellow oil for the majority diastereoisomer with a weight yield. 70% overall. ed = 38 (69-31) determined by 19F NMR on the reaction crude -15-Characterization of compounds 2a1 / 2a2 C38H41 FO8 M = 644.73 g.mor1 2a1-Minor diastereoisomer Rf: 0.53 (cyclohexane / acetate d ' ethyl 7/3) 19F NMR (CDCl3, 282.5 MHz) -200.5 (dd, JF_H = 47 and 2 Hz) 1H NMR (CDCl3, 300MHz) 1.2 (t, 7.2, 3H, CH 3 ); 3.4 (dd, 5.8-9.2 1H, 116); 3.6 (dd, 7.7-9.3, 1H, H6); 3.9 (s, 1H, HI); 4 (dd, 2.6-10, 1H, H3); 4.1 (dd, 6.5, 1H, Hf); 4.2 (m, 2H, CH); 4.3 (d, 11.4, 1H, H2); 4.3-4.9 (m, 8H, 40CH2Ph); 5 (d, 47Hz, 1H, CHF); 7.2 (m, 20H, Har) 13C NMR (CDCl3, 75.5MHz) 14.4 (CH3); 62.9 (CH2); 69.1 (C6); 71.5 (Cf); 73.1 (OCH2Ph); 73.8 (OCH2Ph); 74.8 (C4); 74.9 (OCH2Ph); 75.1 (C2); 76.1 (OCH2Ph); 80.6 (C3); 86.9 (d, 203Hz, CHF); 98.5 (d, 21Hz, C); 127.9 -128.8 (Char.); 138.4; 138.5; 138.8; 139.2 (Char. Quat.); 169.5 (d, 22Hz, CO2Et).

.-Major diastereoisomer Rf = 0.61 (cyclohexane / ethyl acetate 7/3) 19F NMR (CDCl3, 282.5 MHz) -205.2 (d, JF_H = 47 Hz) 1H NMR (CDCl3, 300MHz) 0 , 9 (t, 7.2, 3H, CH3); 3.4 (dd, 5.5-9.1 1H, H6); 3.5 (dd, 9, 1H, H6); 3.6 (s, 1H, OH); 3.9 (qdt, 7.2, 2H, CH2); 4 (m, 2H, H4, H3); 4.1 (dd, 6.7, 1H, H5); 4.3 (d, 9, 1H, H22); 4.4-5 (m, 8H, 40CH Ph); 4.8 (d, 47Hz, 1H, CHF); 7.2 (m, 20H, Har) 13C NMR (CDCl13.75.5MHz) - 16 - 14.1 (CH3); 62.3 (CH2); 68.6 (C6); 71.3 (C5); 72.7 (OCH2Ph); 73.9 (OCH2Ph); 74.3 (CI); 75 (OCH2Ph); 75.2 (C2); 75.4 (OCH2Ph); 81.1 (C3); 88.7 (d, 193Hz, CHF); 97.8 (d, 20Hz, Cl); 127.9 -128.9 (Char.); 138.3; 138.5; 138.6; 139.2 (Char. Quat.); 166.6 (d, 25Hz, CO2Et). The 2a1 / 2e compounds can also be obtained according to another synthetic route which this time leads to the majority 2al and 2a2 minority diastereoisomer.

Synthesis of the 2b1 / 2b2 Compounds (Figure 1) In a flask under an inert atmosphere containing Zinc (2.55 g; 38.96 mmol; 7 eq.) Previously activated and pickled, THF (40 mL) is added. The medium is brought to reflux, then a mixture consisting of lactone lb (3 g; 5.57 mmol; 1 eq.) And ethyl bromofluoroacetate (1.97 mL; 16.7 mmol;) is added dropwise. 3 eq.) In THF (40 mL). The reaction is left at reflux for 3 hours. After returning to ambient temperature, a 1N HCl solution (60 mL) is added to the reaction medium. The mixture is filtered through a Buchner funnel to remove excess zinc. Dichloromethane (40 mL) is added to the solution. The two phases are separated and the aqueous phase is extracted twice again with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated. The mixture is then purified on a silica column with as eluent a cyclohexane / ethyl acetate mixture in proportions of 9.3 to 0.7, to obtain white crystals for the minority diastereoisomer 2b1 and a light yellow oil for the diastereomer. majority with a weight yield of 61%. 25 ed = 46 (73-27) in 19F NMR ed = 54 (77-23) in HPLC (kromasil C18 column, UV 254nm, 90/10 CH3CN / H2O, 1 mL / min) 5 -17-Characterization of 21b1 / 2bz M = 644.73 g.mol "1 2b1 Minor diastereoisomer Rf: 0.23 (cyclohexane / ethyl acetate 8/2). 19F NMR (CDCl3, 282.5 MHz) -200.2 (d, JF_H = 47Hz) 1H NMR (CDCl3, 300MHz) 10 1.2 (t, 7.2, 3H, CH3); 3.5 (dd, 1.5-12.3, 1H, H6); 3.6 (dd, 9.8, 1H, H4); 3.65 (dd, 4.6-11.4.1H, H6); 3.7 (dd, 1.5-9.7, 1H, H2); 4.0 (dd, 2.7-10, 1H, Hf); 4.1 (dd, 9.7, 1H, H3); 4.2 (m, 2H, CH2); 4.4-4.9 (m, 8H, 4OCH2Ph); 4.9 (d, 44, 1H, CHF); 7.2 (m, 20H, Har) 13C NMR (CDCl3, 75.5MHz) 14.5 (CH3); 63.0 (CH2 ); 69.0 (C6); 72.9 (Cf); 73.7 (OCH2Ph); 75.5 (OCH2Ph); 76 (OCH2Ph); 76.1 (OCH2Ph); 78.5 (C2); 78 , 7 (C4); 83 (C3); 86.9 (d, 203 Hz, CHF); 98 (d, 21 Hz, C); 127.9 -128.9 (Çar.); 138.2; 138 , 5; 138.8; 138.9 (Car. Quat.); 163.3 (d, 23Hz, CO2Et).

Major diastereoisomer Rf = 0.17 (cyclohexane / ethyl acetate 8/2). 19F NMR (CDC13, 282.5 MHz) -205.5 (dd, JF_H = 47 and 11 Hz) 1H NMR (CDC13.300MHz) C38H41F08 5 - 18 - 1.1 (t, 7.2, 3H, CHF) ; 3.6 (m, 1H, H6); 3.7 (m, 2H, H4, H6); 3.8 (d, 9.4, 1H, H2); 3.9 (m, 3H, H5.2 Cam); 4.1 (dd, 9.4, 1H, H3); 4.4-5 (m, 8H, 4OCH Ph); 4.8 (d, 47Hz, 1H, CHF); 7.2 (m, 20H, Har) 13C NMR (CDCl 13.75.5MHz) 14.4 (CH3); 62.5 (CH2); 68.7 (C6); 72.9 (C5); 73.7 (OCH2Ph); 75.3 (OCH2Ph); 75.5 (OCH2Ph); 76.1 (OCH2Ph); 78.4 (C4); 78.7 (C2); 83.6 (C3); 86.8 (d, 195Hz, CHF); 97.5 (d, 20Hz, Cl); 127.9 -129.9 (Char.); 138.3; 138.5; 138.7; 138.8 (Char. Quat.); 166.8 (d, 24Hz, CO2Et). The 2b1 / compounds can also be obtained according to another synthetic route which this time leads to the majority 2b1 diastereoisomer and 21mminority.

Synthesis of 2c1 / 2c2 compounds (Figure 1

In a flask under an inert atmosphere containing Zinc (2.55 g; 38.96 mmol; 7 eq.) Previously activated and pickled, THF (40 mL) is added. The medium is brought to reflux, then a mixture consisting of lactone le (3 g; 5.57 mmol; 1 eq.) And ethyl bromofluoroacetate (1.97 mL; 16.7 mmol;) is added dropwise. 3 eq.) In THF (40 mL). The reaction is left at reflux for three hours. After returning to ambient temperature, an iN HCl solution (60 mL) is added to the reaction medium.

The mixture is filtered through a Buchner funnel to remove excess zinc. Dichloromethane (40 mL) is added to the solution. The 2 phases are separated and the aqueous phase is extracted twice again with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated. The mixture is then purified on a silica column with as eluent a cyclohexane / ethyl acetate mixture in proportions of 8.5 to 1.5, to obtain white crystals for the majority diastereoisomer 2c1 and a light yellow oil for the diastereomer. minority 2c with a weight yield of 67% and an ed = 56 (78-22) in 19F NMR -19-Characterization of 2c1 ~ / 2cz C38H41FO8 M = 644.73 g.mol-1 2c1 Major diastereoisomer Rf: 0.53 ( cyclohexane / ethyl acetate 7/3). 19F NMR (CDCl3, 282.5 MHz) -200.0 (d, JF_H = 47Hz) 1H NMR (CDCl3, 300MHz) 1.1 (t, 7.2, 3H, CH3); 3.5 (dd, 1.1-11.5Hz, 1H, H6); 3.7 (dd, 4.4-11.5Hz, 1H, H6); 3.9 (bs, 1H, Ha); 4.0 (m, 2H, 1-15, H1); 4.1 (dd, 2.4-9.5Hz, 1H, H3); 4.1 (dqdt, 2.3-7.2Hz, 2H, CH); 4.3-4.9 (m, 8H, 4OCH2Ph); 5.0 (d, 48Hz, 1H, CHF); 7.2 (m, 20H, Har). 13C NMR (CDCl3, 75.5MHz) 14.4 (CH3); 62.7 (CH2); 69.6 (C6); 73.1 (OCH2Ph); 73.9 (OCH2Ph); 74.0 (Cf); 75.1 and 75.2 (C4 and C2); 75.4 (OCH2Ph); 75.6 (OCH2Ph); 81.6 (C3); 85.6 (d, 181Hz, CHF); 97.9 (d, 26Hz, Cl); 128 -128.9 (Char.); 138.7; 138.8; 138.9; 139.0 (Quat Char.); 169.3 (d, 23Hz, CO2Et). 2c ~ i Minority diastereoisomer Rf = 0.44 (cyclohexane / ethyl acetate 8/2). 19F NMR (CDCl3, 282.5 MHz) -210.3 (d, JF_H = 48Hz) 1H NMR (CDCl3, 300MHz) - 20 - 1.2 (t, 7Hz, 3H, CH3); 3.7 (d, 2.9Hz, 2H, H6); 3.9 (td, 3.2-9.4Hz, 1H, H5); 4 (t, 9.2Hz, 1H, H4); 4 (m, 2H, H2, H3); 4.1 (m, 2H, CH); 4.4-5 (m, 8H, 4OCH2Ph); 5.2 (d, 48Hz, 1H, CHF); 7.2 (m, 20H, Har) 13C NMR (CDCl3, 75.5MHz) 14.5 (CH3); 62.2 (CH2); 69.5 (C6); 73.2 (OCH2Ph); 73.8 (OCH2Ph); 74.2 (C5); 74.4 (OCH2Ph); 75.2 (C4); 75.6 (OCH2Ph); 76 (C2); 82 (C3); 90 (d, 192Hz, CHF); 97.9 (d, 19Hz, Cl); 127.7 -128.8 (Char.); 138.7; 138.8; 138.9; 139.3 (Char. Quat.); 167.1 (d, 24Hz, CO2Et).

Synthesis of compounds 2a1 / 2e and 3a1 / 3a ~ (Figure 2) To a solution of triphenylphosphine (0.5 g, 2 mmol, 4 eq.) In anhydrous THF (5 mL) placed under an inert atmosphere is added the lactone la ( 269 mg, 0.5 mmol, 1 eq.) Solubilized in 2 mL of THF. Et2Zn (C = 1.0 M in hexanes, 2 mmol, 4 eq.) And ethyl dibromofluoroactetate (0.14 mL, 1 mmol, 2 eq.) Are then added successively to the mixture. The medium is stirred at room temperature for three hours, before being hydrolyzed with a saturated aqueous NH4Cl solution, the salts are then filtered through Celite and the filtrate is evaporated under reduced pressure. The reaction mixture reveals the presence of two products: 90% of products 2a1 / 2a2 in the form of two diastereoisomers: 2a1 the major diastereoisomer and 2 the minor diastereoisomer (ed: 94/6 determined in 19F NMR) and 10% of the product 3a1 / 3a2 in the form of two isomers (ed = 60 (80-20) in 19F NMR).

The product 2a1 / gas are purified on silica gel with as eluent a mixture of cyclohexane / ethyl acetate in proportions of eight to two) in order to have a weight yield of 56%. The 2a1 / 2az products have already been characterized previously. The 3a1 / 3az products are purified on silica gel with as eluent a mixture of cyclohexane / ethyl acetate in proportions of nine percent and obtained in the form of a mixture of two diastereomers with a yield by weight of 20%. 2900406 -21- Characterization of compounds 3a1 / 312 5 C38H39FO7 M: 626.73g.morl Rf: 0.6 (cyclohexane / ethyl acetate 8/2), 19F NMR (CDC, 282.5Mz) Majority diastereoisomer 3a,: -144.2 ppm Minor diastereoisomer -144.6 ppm 1H NMR (CDCl3, 300Mz): 1.2 (2t, 0.8H, J = 7.2Hz, CI-13); 3.8-3.6 (m, 3H, H6 and H4); 3.8 (m, 1H, H3); 4.1 (dq, 2H, J = 7.3Hz, CHI); 4.3 (m, 1H, Hf); 4.6-4.4 (m, 8H, 4OCH Ph); 7.3 (m, 20H, Mar 15). 13C NMR (CDCl3, 75.5Mz): 14.4 (CH3); 14.6 (CH3a1; 61.8 (CH2a1; 63.1 (CH2); 69.2 (C6); 70.8 (C2); 71.2 (CH2-Ph); 72.0 (CH2-Ph) ; 72.5 (CH2-Ph); 73.8 (CH2-Ph); 70.8 (C4); 72.8 (CS); 78.4 (CM); 79.4 (C3; 128.8-127, 8 (20 Char.); 138.7-138.2 (Quat. Char.); 147.7 (d, J = - 20 7.92 Hz, Cl); 162.1 (d, J = 26.87 Hz, CO2Et).

Synthesis of compounds 2b1 / 2b2 and 3b, (Figure 2): To a solution of triphenylphosphine (0.5 g, 2 mmol, 4 eq) in anhydrous THF (5 mL) placed under an inert atmosphere is added the lactone lb (269 mg , 0.5 mmol, 1 eq.) Solubilized in 2 mL of THF. Et2Zn (C = 1.0 M in hexanes, 2 mmol, 4 eq.) and ethyl dibromofluoroactetate (0.14 mL, 1 mmol, 2 eq.) are then added successively to the mixture. The medium is stirred at room temperature for three hours, before being hydrolyzed with a saturated aqueous NH4Cl solution, the salts are then filtered through Celite and the filtrate is evaporated under reduced pressure. The crude medium reveals the presence of two products: 90% of the product 2b1 / b2 in the form of two diastereomers (ed: 91/9) and 10% of the product 3b1 in the form of a single isomer. The product 2b, / 2bz are purified on silica gel with as eluent a cyclohexane / ethyl acetate mixture in proportions of 8.5 to 1.5 in order to obtain the compound in the form of a mixture of two b1 / diastereomers. b2 with a weight yield of 58%. Under these reaction conditions, compound 2b1 is the major diastereoisomer and the minor diastereoisomer. The 2b1 / 2b2 products have already been characterized previously.

Product 3b is purified on silica gel with a cyclohexane / ethyl acetate mixture as eluent in proportions of 9.8 to 0.2 in order to obtain the compound in the form of a single isomer with a weight yield of 20%. Characterization of compound 3b, 2 BnO '_4 "OBn 3134 OBn 20 C38H39F07 M: 626.73g.mo1-' Rf: 0.4 (cyclohexane / ethyl acetate 8/2). 19F NMR (CDCl3, 282.5Mz): - 149.8 ppm 1H NMR (CDCl3, 300Mz): 1.2 (t, 0.8H, J = 7.2Hz, CH3); 3.8-3.6 (m, 3H, H6 and H4); 3 , 8 (m, 1H, H3); 4.1 (dq, 2H, J = 7.0-1.9Hz, CHI); 4.3 (m, 1H, Hf); 4.6-4.4 (m , 8H, 4OCH2Ph); 5.6 (s, H2); 7.3 (m, 20H, Har.). 13C NMR (C) C13, 75.5Mz): 14.6 (CH3); 61, 4 (CH2); 68.6 (C6); 70.7 (C2); 71.0 (OCH2Ph); 71.5 (OCH2Ph); 73.0 (OCH2Ph); 73.7 (OCH2Ph); 76.1 (Ci); 78.2 (CI); 81.4 (C3); 128.8-128.1 (Char.); - 23 - 138.6; 138.2; 138.1; 137.6; 137 , 3 (Çar.q.); 137.3 (d, J = 252Hz, CF); 147.5 (d, J = 8Hz, Cl); 162.5 (d, J = 27Hz, CO2Et). compounds 2c1 / 2cz and 3c1 / 3c ~ ripe 2) Lactone le (269 mg; 0) is added to a solution of triphenylphosphine (0.5 g; 2 mmol; 4 eq) in anhydrous THF (5 mL) placed under an inert atmosphere. , 5 mmol; 1 eq.) Solubilized in 2 ml of THF. Et2Zn (C = 1.0 M in hexanes, 2 mmol, 4 eq.) And Ethyl dibromofluoroactetate (0.14 mL; 1 mmol; 2 eq.) Are then added successively to the mixture. The medium is stirred at room temperature for three hours, before being hydrolyzed with a saturated aqueous NH4Cl solution, the salts are then filtered through Celite and the filtrate is evaporated under reduced pressure. The crude medium reveals the presence of two products: 88% of the 2c1 / ç2 products as two diastereomers (ed: 75/25) and 12% of the 3c1 / 3c2 product as two isomers (78/22). The 2c1 / 2e2 products are purified on silica gel with as eluent a cyclohexane / ethyl acetate mixture in the proportions 8.5 to 1.5 in order to obtain the 20 compounds 2c1 / 2c2 in the form of two diastereoisomers with a yield. by 66%. This time, the process results in the same majority and minority daistereomer 2e1 as by the previous method. The 2c1 / 2c2 products have already been characterized previously.

The 3c1 / fc products are purified on silica gel with as eluent a cyclohexane / ethyl acetate mixture in proportions of nine to one in order to obtain the compound in the form of a mixture of two isomers (ed = 78/22 in 19F NMR) with a weight yield of 12%. - 24 -Characterization of 3c1 / 3c2 compounds M: 626.73g.mor 'C38H39FO7 Rf: 0.6 (cyclohexane / ethyl acetate 8/2), 19F NMR (CDC13, 282, SMz): Minor 3c1 diastereoisomer: - 143.9 ppm Majority diastereomer: -149.5 ppm 1H NMR (CDCl3, 300Mz): 1.2 (t, 1H, J = 7.1Hz, CH3); 3.8-3.6 (m, 3H, H6 and H4); 3.9 (t, J = 4.2Hz, H3); 4.1-4.3 (m, 2H, CH2); 4.6-4.4 (m, 8H, 4OCH2Ph); 4.9 (td, 1H, J = 6.64, 4.47, 4.47 Hz, Hf); 5.71 (dd, 1H, J = 3.31, 2.60Hz, H2); 7.3 (m, 20H, Har). 13C NMR (CDCl3.7S, SMz): 14.6 (CH3); 61.7 (CH2); 68.2 (C2); 68.8 (C6); 71.0 (CH2-Ph); 71.6 (CH2-Ph); 72.9 (CH2-Ph); 73.9 (CH2-Ph); 78.0 (C4); 78.2 (CS); 79.9 (d, J = 3.6Hz, C3); 128.8-128.0 (20 Char.); 138.4; 138.3; 138.2; 137, 7 (4th Char.); 136.47 (d, J = 254.24Hz, CF); 147.89 (d, J = 7.92Hz, Cl); 162.43 (d, J = 26.87 Hz, CO2Et). Synthesis of compounds 4a1 / 4a ~ (Figure 3):

In a flask under an inert atmosphere containing the lactone la (269 mg, 0.5 mmol, 1 eq.) Dissolved in THF (5 mL), the diethylzinc Et2Zn (C = 1.0 M in hexanes, 1 mmol, 2 eq.) And ethyl dibromofluoroactetate (0.14 mL, 1 mmol, 2 eq.) Are added successively to the mixture. The solution is then stirred at room temperature for three hours before being hydrolyzed with Ethanol, and evaporated under reduced pressure. The mixture is then purified on silica gel with as eluent a cyclohexane / ethyl acetate mixture in proportions of 9.5 to 0.5 in order to obtain compounds 4a1 / 4a2 in the form of a mixture of two diastereoisomers ( ed = 50 (75-25) in 19F NMR) with a yield of 62%. BnO vi / CO2Et 2 BnO ~ 4 i 'OBn OBn -1 C38H40FBrO8 M = 723.74 g, moF1 Rf: 0.4 (cyclohexane / ethyl acetate 8/2), 19F NMR (CDC, 282.5Mz): Majority diastereoisomer 4a1: - 126.5 ppm Minority diastereoisomer 4th: - 126.7 ppm 1H NMR (CDCl3, 300Mz): 1.1 (t, 0.8H, J = 7.2Hz, CH3a2); 2.2 (t, 1.2H, J = 7.2Hz, CH3a1); 3.6-3.5 (dd, 1H, J = 7-12Hz, H6); 3.9-3.7 (dd, 1H, J = 7.3Hz, H6); 4.0 (s, 1H, H4); 4.0 (m, 1H, H3); 4.0 (m, 1H, H5); 4.1 (q, 2H, J = 7.3Hz, CH2); 4.2 (m, 1H, H2); 4.3-4.8 (m, 8H, 4OCH2Ph); 7.3 (m, 20H, Har.). 13C NMR (CDCl3, 75.5): Mz Major diastereoisomer 4a1: 14.2 (CH3); 64.0 (CH2); 68.9 (C6); 72.4 (C5); 73.5 (OCH2Ph); 73.8 (OCH2Ph); 74.4 (C4); 74.9 (OCH2Ph); 75.5 (C2); 75.7 (OCH2Ph); 81.4 (C); 98.0 (d, J = 274Hz, CF); 98.5 (d, J = 25Hz, Cl); 127-129 (Char.); 139-138 (Çar.quat.); 166.4 (d, J = 26Hz, CO2Et). Minority diastereoisomer 4al: F Br 4a / 4a - 26 - 13.9 (CH3); 63.8 (CH2): 68.7 (C6); 72.2 (C5); 72.8 (OCH2Ph); 74.0 (OCH2Ph); 74.8 (OCH2Ph); 75.0 (C4); 75.1 (OCH2Ph); 75.5 (C2); 81.9 (C3); 99.0 (d, J = 295Hz, CF); 98.0 (d, J = 23Hz, Cl); 127-129 (Char.); 139-138 (Car.quat.); 165.6 (d, J = 26Hz, CO2Et).

Synthesis of compounds 4b1 / 4b ~ (Figure 3): In a flask under an inert atmosphere containing lactone lb (269 mg, 0.5 mmol, 1 eq.) In solution in THF (5mL), Et2Zn (C = 1 , 0 M in hexanes, 1 mmol, 2 eq.) And ethyl dibromofluoroactetate (0.14 mL, 1 mmol, 2 eq.) Are added successively to the mixture. The solution is then stirred at room temperature for three hours before being hydrolyzed with ethanol, and evaporated under reduced pressure.

The mixture is then purified on silica gel with as eluent a cyclohexane / ethyl acetate mixture in proportions of 9.5 to 0.5 in order to obtain the compounds 4b1 / 4b2 in the form of a mixture of two diastereoisomers ( ed = (92-8) in 19F NMR) with a yield of 41%.

Characterization of compounds 4b1 / 4b2 C38H40FBrO8 M = 723.74 g, mol "'Rf: 0.37 (cyclohexane / ethyl acetate 8/2), 25 NMR 19F (CDCl3, 282.5Mz): Minor diastereoisomer 4b1: - 127.2 ppm Majority diastereoisomer: -127.8 ppm 1H NMR (CDCl3, 300Mz): 20 -27-1.1 (t, 0.8H, J = 7.2Hz, CH3b1); 2.2 (t, 1.2H, J = 7.2Hz,, CH312.); 3.6-3.5 (dd, 1H, J = 7-12Hz, H6); 3.9-3.7 (dd, 1H, J = 7.3Hz, H6); 4.0 (s, 1H, H4); 4.0 (m, 1H, H3); 4.0 (m, 1H, Hf); 4.1 (q, 2H, J = 7.3Hz, Crn); 4.2 (m, 1H, H2); 4.3-4.8 (m, 8H, 4OCH2Ph); 7.3 (m, 20H, Har.).

13C NMR (CDCl3, 75.5Mz): Minority diastereoisomer 4b1: 13.9 (CH3); 63.8 (CH2); 68.7 (C6); 72.2 (C5); 72.8 (OCH2Ph); 74.0 (OCH2Ph); 74.8 (OCH2Ph); 75.0 (C4); 75.1 (OCH2Ph); 75.5 (C2); 81.9 (C3); 99.0 (d, J = 295Hz, CF); 98.0 (d, J = 23Hz, Cl); 127-129 (Car.); 139-138 (Car.quat.); 165.6 (d, J = 26Hz, CO2Et). Majority diastereomer 4: 14.2 (HH3); 64.0 (CH2); 68.9 (C6); 72.4 (Cf); 73.5 (OCH2Ph); 73.8 (OCH2Ph); 74.4 (CI); 74.9 (OCH2Ph); 75.5 (C2); 75.7 (OCH2Ph); 81.4 (C3); 98.0 (d, J = 274Hz, CF; 98.5 (d, J = 25Hz, Cl); 127-129 (Çar.); 139-138 (Car.quat.); 166.4 (d, J = 26Hz, CO2Et).

Synthesis of 4c1 / 4c2 compounds (Figure 3)

In a flask under an inert atmosphere containing the lactone le (269 mg; 0.5 mmol; 1 eq.) Dissolved in THF (5 mL), the Et2Zn (C = 1.0 M in hexanes, 1 mmol, 2 eq. .) and ethyl dibromofluoroactetate (0.14 mL; 1 mmol; 2 eq.) are added successively to the mixture. The solution is then stirred at room temperature for three hours before being hydrolyzed with ethanol, and evaporated under reduced pressure.

The mixture is then purified on silica gel with the cyclohexane / ethyl acetate mixture as eluent in proportions of 9.5 to 0.5 in order to obtain the compound in the form of a mixture of two diastereomers (ed = (42- 58) in 19F NMR) 4c1 / 4c2 with a yield by weight of 43%. 30 -28-Characterization of compounds 4c1 / 4c2 BnO 4Y '' OBn 4c, / 4c2 OBn C38H40FBrO8 M = 723.74 g, moFl Rf: 0, 34 (cyclohexane / ethyl acetate 8/2), 19F NMR (CDCl3, 282.5Mz): Minor diastereoisomer 4c1: -120.3 ppm Major diastereoisomer 4: -124.9 ppm 1H NMR (CDCl3, 300Mz) 0, 9 (t, 1H, J = 7.1Hz, CH3c; 1.1 (t, 1.2H, J = 7.1Hz, CH ci; 3.6-3.5 (dd, 1H, J = 7-12Hz , H6); 3.9-3.7 (dd, 1H, J = 7.3Hz, H6); 4.0 (s, 1H, H4); 4.0 (m, 1H, H3); 4.0 (m, 1H, Hf); 4.1 (q, 2H, J = 7.3Hz, CHI); 4.2 (m, 1H, H2); 4.3-4.9 (m, 8H, 4 OCH Ph); 7.3-7.1 (m, 20H, Har). 13C NMR (CDCl3, 75.5Mz): Minor diastereoisomer 4c1: 14.1 (CH3); 64.0 (CH2); 69.2 ( ÇH2); 73.4 (OCH2Ph); 74.0 (OCH2Ph); 74.6 (Cf); 74.8 (OCH2Ph); 75.1 (C 4); 75.6 (OCH2Ph); 76.7 (C2); 82.2 (C3); 98.2 (d, J = 20Hz, Cl); 103.2 (d, J = 282Hz, CF); 128.9-127.8 (Char.); 139.1-138.6 (Car.quat.); 165.0 (d, J = 25Hz, CO2Et). Majority diastereoisomer 4c ~: 14.0 (CH3); 63.6 (CH2); 69.5 (C6); 73.3 (OCH2Ph); 73.8 (OCH2Ph); 74.8 (OCH2Ph); 74.9 (C5); 75.0 (C2); 75.6 (OCH2Ph); 82.0 (C3J; 98.9 (d, J = 25Hz, Cl); 100.6 (d, J = 272Hz, CF); 127-129 (Char.); 139-138 (Char.quat.); 165.7 (d, J = 27Hz, CO2Et). -29- Synthesis of compounds 5a1 Sa2 (Figure 4) In a flask containing ester 2a, / le (500mg; 0.776mmol; leq.) In solution in THF (5 mL), a solution consisting of LiOH (37 mg; 1.55 mmol; 2 eq.) Dissolved in the minimum amount of water is added. The reaction is kept under stirring overnight. A 1M HCl solution is added and the mixture is stirred. the medium is extracted three times with ethyl acetate The organic phases are combined, dried over magnesium sulphate, filtered and then evaporated to obtain the expected product in the form of a yellow oil with a yield of 96%.

Characterization of compounds 5a1 / Sa2 C36H37FO8 M = 616.67 g.moï1 NMR 19F (CDCl3, 282.5MHz) -197.9 (d, JF_H = 49 Hz, 1F): 5a, -202.7 (d, JF_H = 47Hz, IF): Sad 1H NMR (CDCl3, 300MHz) 3.4 (dd, 2.2-6.2 2H, H6); 3.8 (s, 1H, H4); 3.9 (dd, 2.4 and10Hz, 1H, H3); 4.1 (tapp., 6.1Hz, 1H, Hf); 4.2 (dd, 2.8 & Hz, 1H, H2); 4.3 (d, 11.9Hz, 1H, OCH2Ph); 4.4 (d, 12Hz, 1H, OCjPh); 4.5 (d, 11.7Hz, 1H, OCH Ph); 4.6 (d, 11.1Hz, 1H, OCL12Ph); 4.7 (s, 2H, OC ~ Ph); 4.8 (d, 12Hz, 1H, OCH2Ph); 4.9 (d, 11.2Hz, 1H, OCH Ph); 4.9 (d, 47Hz, 1H, CHF); 7.2 (m, 20H, Har). 13C NMR (CDCl 13.75.5MHz) 69.2 (C6); 71.5 (C5); 73.2 (OCH2Ph); 73.7 (OCH2Ph); 74.8 (OCH2Ph); 74.9 (C4); 75.2 (C2); 76.2 (OCH2Ph); 80.6 (C3); 86.0 (d, 200Hz, CHF); 98.4 (d, 21Hz, Cl); 128.0 -128.9 (Char.); 137.9; 138.3; 138.7; 139.0 (Quat Char.); 171.0 (d, 24Hz, CO2H). - 30 - Synthesis of compound 5b, (Fig. 4) In a flask under an inert atmosphere containing the ester 2b1 (275 mg; 0.43 mmol; 1 eq.) Dissolved in ethanol (7 mL), an aqueous solution of lithine (2M; 2 eq.) is added and the mixture is stirred overnight at room temperature. The medium is concentrated and dissolved in DCM (5 mL), it is then acidified with a 1M HCl solution (20 mL). The mixture is extracted with DCM (3 x 20 mL), and the organic phases are combined, washed with saturated NaCl solution and concentrated directly. The Shi acid is thus isolated as a yellow solid which can be used directly for the next step without additional purifications with a crude yield of 92%. Characterization of compound 5b1 19F NMR (CDCl ~, 282MHz) -197.9 (d, 2JRH 46.1). 1H NMR (CDCl3, 300MHz) 3.42-3.71 (m, 4H), 3.94-4.09 (m, 2H), 4.29-4.91 (m, 9H), 7.03-7.28 (m, 20H, H, r). Synthesis of compounds 6a2 (Figure 5) In a flask under an inert atmosphere containing the monofluoroester (230 mg; 0.36 mmol: 1 eq.) In solution in anhydrous dichloromethane (3 mL) at -30 C, the mixture is added dropwise. by drop the SOBr2 (41 L; 0.535 mmol; 1.5 eq.). After 30 minutes, the pyridine (42 L; 0.535 mmol; 1.5 eq.) Is introduced. and the mixture is left under stirring for a further 30 minutes at -30 C. A 2M HCl solution is added and the phase is extracted three times with dichloromethane. The organic phases are combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is obtained in the form of a light yellow oil with a weight yield of 80%. Characterization of compound 6a2 C38H40BrFO7 M = 706.62 g.mol-1 19F NMR (CDCl3 282MHz) -188.0 (d, 45Hz). 1H NMR (CDCl3, 300MHz) 0.97 (t, 7.1Hz, 3H, C. 113); 3.51 (dd, 5.4 & 9.1Hz, 1H, 1H6); 3.60 (tapp, 8.6Hz, 1H, 1H6.); 3.91-4.1 (m, 5H, H4, H3, Cam, H5); 4.22 (d, 9.4Hz, 1H, H2); 4.37 (d, 11.8Hz, 1H, OCLI2Ph); 4.43 (d, 11.8Hz, 1H, OCH Ph); 4.45 (d, 11Hz, 1H, OCH Ph); 4.63 (d, 11.5Hz, 1H, OCH Ph); 4.68 (d, 11.8Hz, 1H, OCLI2Ph); 4.78 (d, 11.6Hz, 1H, OCH2Ph); 4.86 (d, 11Hz, 1H, OCH2Ph); 5.01 (d, 11.5Hz, 1H, OCH Ph); 5.07 (d, 46Hz, 1H, CHF); 7.2 (m, 20H, Har) 13C NMR (CDCl13.75.5MHz) 14.2 (CH3); 62.7 (CH2); 67.4 (C6); 73.0 (OCH2Ph); 73.6 (C4); 74.0 (OCH2Ph);

25 0.775 mmol: 1 eq.) In solution in anhydrous dichloromethane (6 ml) at -30 ° C., SOBr2 (88 L; 1.13 mmol; 1.5 eq.) Is added dropwise. After 30 minutes, the pyridine (92 L; 1.13 mmol; 1.5 eq.) Is introduced and the mixture is left stirring for a further 30 minutes at -30 C. A 2M HCl solution is added and the phase is extracted. three times with dichloromethane. The organic phases are combined, dried over MgSO4, filtered and concentrated under reduced pressure. 75.0 (OCH2Ph); 75.3 (OCH2Ph); 76.2 (C2); 76.4 (C5); 82.3 (C3); 89.5 (d, 199Hz, CHF); 106.9 (d, 18Hz, Cl); 127.5 -128.9 (Char.); 138.0; 138.3; 138.7; 138, 9 (Char. Quat.); 164.9 (d, 27Hz, CO2Et). mosé 6b (Figure 5) Synthesis of co p z In a flask under an inert atmosphere containing the monofluoroester (500 mg;

The crude product is obtained in the form of a brown oil with a weight yield of 85%. Characterization of compound 6b2 C38H40BrFO7 M = 706.62 g.mor '19F NMR (CDCl3, 282MHz) -188.09 (d, 45Hz). 1H NMR (CDCl3, 300MHz) 10 1.1 (t, 7.1Hz, 3H, CH3); 3.6 (dd, 1.7-11.5Hz, 1H, 1H6); 3.7 (m, 2H, H2, 1H6); 3.8 (dd, 9Hz, 1H, H4); 3.9 (td, 2.2-10.1Hz, 1H, H5); 4.1 (qdt, 7.1Hz, 2H, CH2); 4.1 (dd, 9.2, 1H, H3); 4.4-5 (m, 8H, 4OCH2Ph); 5.06 (d, 46Hz, 1H, CHF); 7.2 (m, 20H, Har) 13C NMR (CDCl 13.75.5MHz) 14.4 (CH3); 62.8 (CH2); 67.7 (C6); 73.7 (OCH2Ph); 75 (OCH2Ph); 75.7 (OCH2Ph); 76.2 (OCH2Ph); 76.6 (C2); 78.1 (C5); 79.9 (C4); 84.7 (C3); 89.5 (d, 203Hz, CHF); 105.7 (d, 18Hz, Cl); 127.5 -128.9 (Char.); 138.2; 138.4; 138.5 (Char. Quat.); 165.4 (d, 26Hz, CO2Et). The same reaction carried out under the same conditions on compound 2b1 results in compound 6b1. 19F NMR (C (CDCl3, 282MHz) -182.2 (d, 47Hz). Synthesis of compound 7a2 (Figure 6) In a flask under an inert atmosphere containing the monofluoroester (95 mg; 0.147 mmol: 1 eq.) In solution in anhydrous dichloromethane (2mL) at -30 C, thionyl chloride SOC12 (16 L; 0.221 mmol; 1.5 30 eq.) is added dropwise. After 30 minutes, the pyridine (17 L; 0.221 is introduced). mmol; 1.5 eq.) and the mixture is left stirring for another 30 minutes, still at -30 C. A 2M HCl solution is added and the phase is extracted three times with dichloromethane. combined, dried over MgSO4, filtered and concentrated under reduced pressure The crude product is obtained in the form of a light yellow oil with a weight yield of 83%.

Characterization of compound 7a2 C38H40C1F07 M = 663.17 g.mo1-1 19F NMR (CDCl3, 282MHz) -194.9 (d, 1F, 46Hz) 1H NMR (CDCl3, 300MHz) 0.98 (t, 7.1Hz, 3H, CH3); 3.50 (dd, 5.4-9.1, 1H, 116); 3.58 (tapp., 8.6Hz, 1H, H6); 3.92-4.09 (m, 4H, H4_1112, CH 2); 4.16 (m, 1H, H5); 4.37 (d, 11.8Hz, 1H, OCH-Ph); 4.43 (d, 11.4Hz, 1H, OCHPh); 4.46 (d, 10.9Hz, 1H, OCH2Ph); 4.48 (d, 9.3Hz, 1H, H2); 4.63 (d, 11.4Hz, 1H, OCHPh); 4.68 (d, 11.4Hz, 1H, OCHPh); 4.75 (d, 11.5Hz, 1H, OCH2Ph); 4.86 (d, 11.1Hz, 1H, OCH2Ph); 4.99 (d, 11.4Hz, 1H, OCH-Ph); 5.02 (d, 46Hz, 1H, CHF); 7.23 (m, 20H, Har) 13C NMR (CDCl3.75.5MHz) 14.2 (CH3); 62.6 (CH2); 67.6 (C6); 73.0 (OCH2Ph); 73.8; 74.0 (OCH2Ph) 74.4; 75.2 (2OCH2Ph); 76.0; 81.3; 89.2 (d, 200Hz; CFH); 127.7-128.9 (Car.); 138.3; 138.6; 139.0 (Car quat.); 161.4 and 161.9 (2t, 32 Hz, CO2Et).

Synthesis of compound 7b1 / 7h2 (Figure 6) The mixture of the two diastereomers of ester 21_21 / 22b (500 mg; 0.77 mmol; 1 eq.) Is placed in dichloromethane (20 mL) and added thionyl halide ( 138 mg; 1.16 mmol; 1.5 eq.) At -30 C. After 30 min at -30 C, pyridine (92 mg; 1.16 mmol; 1.5 eq.) Is added and the solution is stirred for an additional 30 min. The solution is hydrolyzed with 2N HCl (20 mL) then extracted with dichloromethane (3 x 20 mL). The organic phases are washed with saturated sodium chloride solution (30 mL) then dried over sodium sulfate and concentrated. The reaction crude is then purified by chromatography column on silica gel with a cyclohexane / ethyl acetate (80:20) eluent.

The 2 diatereomers 2b1 / 2bz are isolated in the form of a colorless oil with a yield of 78%.

Characterization of compound 7b1 / 7b C38H40C1F07 M = 663.17 g.mol_1 10 Rf = 0.50, eluent: cyclohexane / ethyl acetate (8: 2). 19F NMR (CDC13, 282MHz) -186.4 (1F, d, 2JF_H7 47.2) 7b1 -195.0 (IF, d, 2JF-H7 46.1) 7bz 1H NMR (CDC13, 300MHz) 15 1.10 (t, 3H, 3JHlo-Hlo 7.2, CH3), 1.11-1.21 (m, 3H, CHI), 3.55-3.78 (m, 3H, n6), 3.91-4.08 (m, 3H), 4.19 (q, 2H, 3JH9-H10 7.2, CH3), 4.39- 4.57 (m, 4H), 4.67-5.20 (m, 5H, H7), 7.20-7.25 (20I1). 13C NMR (CDCl3, 75MHz) 14.4 (CH3), 14.5 (CH3), 62.4 (CH3), 62.8 (CH3), 67.9 (C6), 68.2 (C6), 73.7, 73.9, 20 74.7, 75.4, 76.3, 79.3, 79.6, 83.0, 83.5, 88.9 (d, 1JC7-F 201.0, CF), 89.2 (d, 1JC7_F 195.9, CF), 103.0 (d, 2JC1_F 22.8, Cl), 105.0 (d, 2JC1_F 18.3, Cl), 127.3, 127.7, 127.7, 127.8, 127.8, 127.8, 127.9, 127.9, 128.0, 128.0, 128.1, 128.1, 128.3, 128.4, 128.5, 128.5, 128.6, 137.8, 137.9, 138.0, 138.1, 138.2, 138.3, 138.3, 138.3, 165.1 ( d, 2JC8-F 33.1, CO2Et), 165.5 (d, 2JC8_F 33.1, CO2Et). 25 -35- Synthesis of the compound 8b1 / 8b ~ (Figure 7) The chlorinated product 7b1 / h (240 mg; 0.36 mmol; 1.0 eq.) Is placed with tributyl tin (422 mg; 1.50 mmol; 4.0 eq.) In dry toluene (20 mL) and the solution is refluxed for four hours. After returning to ambient temperature, the medium is concentrated and purified by chromatographic column on silica gel with a cyclohexane / ethyl acetate eluent (80:20). The product is isolated with 63% yield. The reaction can be carried out under the same conditions from the brominated 6 eebz derivatives to lead to the same compounds 8b1 / 8b2 Characterization of the compound 8b1 / 8b2 C38H41FO7 M = 628 g.mol-1 Rf = 0.43, eluent: cyclohexane / acetate d ' ethyl (8: 2). 19F NMR (CDCl3, 282MHz) -203.1 (1F, dd, 2JF-H7 48.7, 3JF_H1 23.6) 8b ~. 15 -208.4 (1F, dd, 2JF-H7 48.0, 3JF-H1 31.1) 8b1. 1H NMR (CDCl3, 300MHz) 1.03 (t, 3H, 3JH10-H9 7.2, CH3), 1.15 (t, 3H, 3JH10419 6.7, CH), 3.50-3.72 (m, 7H, H2, H3, H4, H5 , 2H6), 3.88 (qapp, 2H, 3JH9-H10 6.7, Cam, 4.15 (dd, 2H, 3JH94H10 7.2, 3.2, Cr), 4.45-4.64 (m, 4H), 4.72-4.88 (m, 5H), 5.08 (d, 1H, 2JH7-F 48.0, CFH 5.08 (d, 20 1H, 2JH7_F 48.7, CFH), 7.10-7.28 (m, 20H, Ar). 13C NMR (CDCl3, 75MHz) 14.4 (CH3), 14.6 (CIO ), 61.6 (CH3), 61.8 (CH2), 68.9 (C6), 73.8, 74.0, 75.0, 75.6, 75.7, 76.1, 76.8 (d, JC_F 7.0), 77.5 (d, JC_F 4.0), 78.6, 78.8, 79.4 , 79.6, 79.9, 80.5, 87.0 (d, 1JC7_F 191.8, CF), 87.5 (d, 2Jc1_F 22.1, Cl), 88.6 (d, 1Jc74, 190.8, CF), 127.6, 25

24.6, CO2Et), 167.7 (d, 2JC8_F 24.6, CO2Et). 127.6, 127.7, 127.8, 127.8, 127.9, 127.9, 128.0, 128.0, 128.1, 128.2, 128.2, 128.3, 128.4, 128.5, 128.6, 128.6, 128.7, 137.9, 138.0, 138.2, 138.2, 138.3, 167.0 (d, 2JC8- F -36 - Synthesis of compound 9b1 / 9b ~ (Figure 8)

In a flask under an inert atmosphere containing the ester 8b / i gb2_ (140 mg; 0.223 mmol; 1 eq.) In solution in ethanol (12 ml), an aqueous solution of lithine (2M; 2 eq.) Is added. and the mixture is stirred overnight at room temperature. The medium is concentrated and dissolved in DCM (15 mL), it is then acidified with a 2M HCl solution (20 mL). The mixture is extracted with DCM (3 x 20 mL), and the organic phases are combined, washed with saturated NaCl solution (30 mL) and concentrated directly. The 9b1 / 9b2_ acid is thus isolated as a colorless oil with a crude yield of 99%.

Characterization of compound 9b1 / 9b2 C36H37FO7 M = 600 g.mor '19F NMR (CDCl3, 282MHz) -202.1 (1F, dd, 2JF_H7 45.1, 3JF_H1 19.3). -207.2 (1F, dd, 2JF_H7 46.1, 3JF_H1 30.0) 9b1. 1H NMR (CDCl3, 300MHz) 3.46-3.72 (m, 7H, H1, H2, H3, H4, H5, 2H6), 4.43-4.50 (m, 2H), 4.54-4.87 (m, 6H), 5.02 (d, 2JH7_F 47.8, CHI), 5.06 (d, 2JH7_F 48.5, CFH), 7.09-7.31 (20Hj). NMR13C (CDC13, 75MHz) 68.6, 68.8, 73.3, 73.6, 74.8, 75.3, 75.4, 75.8, 76.4, 76.5, 77.5, 77.5, 78.2, 78.7, 79.0, 79.5, 79.7, 86.3 (d, 'JC74 191.0, CF) , 86.6 (d, 2JCI_F 18.8, Cl), 87.7 (d, 'JC7_F 191.9, C7), 127.5, 127.6, 127.8, 127.8, 127.9, 128.0, 128.1, 128.1, 128.2, 128.2, 128.4, 128.5, 128.6, 128.6, 128.7, 137.8, 137.9, 138.3, 138.4, 171.5 (d, 2JC8_F 24.6, CO2Et). - 37 -Synthesis of lObi compounds (Figure 9)

In a flask under an inert atmosphere containing the ester (290 mg; 0.45 mmol; 1 eq.) Dissolved in anhydrous toluene (5 mL) at -78 C, a solution of 1M DIBAL-H in toluene is added ( 1.35 mL; 1.35 mmol; 3 eq.). The medium is left under stirring at -78 ° C. for 2:30 minutes, then a solution of DIBAL-H is again added (450 L; 0.45 mmol; 1 eq.). The medium is stirred for 30 min at -78 ° C. then ethanol is added (2 ml). The solution is brought up to -20 C for 10 minutes, and a 20% solution of Rochelles salts (40 mL) is added. The mixture is left under vigorous stirring for several hours. The ethyl acetate is added (20mL), then after decantation, the aqueous phase is extracted twice with ethyl acetate (2 * 15rnL). Then the organic phases are combined and washed twice with an aqueous solution. saturated with NaCl (2 * 15mL), dried over magnesium sulfate, filtered and then evaporated. Characterization of 10b2 C36H37FO7 M = 600.67 g.mol-1 19F NMR (CDC13, 282.5 MHz) -211.4 (dd, JF_H = 48Hz and 8Hz) 1H NMR (CDC13, 300MHz) 20 3.57-3 , 62 (m, 4H, H6, H2, H4); 3.96 (m, 1H, Hf); 3.97 (t, 9.1Hz, 1H, H3); 4.44 (d, 12.3Hz, 1H, OCH Ph); 4.48 (d, 12.3Hz, 1H, OCHZPh); 4.50 (d, 11.8Hz, 1H, OCH2Ph); 4.53 (d, 10.8Hz, 1H, OCHzPh); 4.6 (d, 49Hz, 1H, CHF); 4.72 (d, 10.8Hz, 1H, OCH2Ph); 4.77 (d, 11.2Hz, 1H, OCHZPh); 4.85 (d, 11.1Hz, 1H, OCHZPh); 7.07-7.25 (m, 20H, Har); 9.45 (d, 7.4Hz, 1H, CHO). 13C NMR (CDCl3, 75.5MHz) 15 - 38 - 68.8 (C6); 72.6 (C5); 73.8 (OCH2Ph); 75.4 (OCH2Ph); 75.5 (OCH2Ph); 76.0 (OCH2Ph); 77.9 (C2); 78.4 (C4); 83.5 (C3); 94.1 (d, 192Hz, CHF); 98.2 (d, 20Hz, Cl); 128.0 -128.9 (Char.); 137.6; 138.3; 138.4; 138.6 (Char. Quat.); 196.2 (d, 30Hz, CHO).

Synthesis of compounds 10a1 (Figure 11) In a flask under an inert atmosphere at -78 C, containing DMSO (121.1L; 0.16mmol; 5eq.) In dichloromethane (1mL), a solution of oxalyl chloride (7 L , 0.073mmol; 2.2eq.) In dichloromethane (lmL) is added. The reaction medium is stirred for 15 min at -78 C, then the alcohol II (20 mg; 0.033 mmol; 1 eq.) Is added. The temperature is allowed to rise to -40 ° C. over 1 hour, then the triethylamine (241.tL; 0.17mmol, 5 eq.) Is introduced. The temperature is allowed to return to ambient in two hours, and a saturated solution of NaCl is added. The medium is extracted three times with dichloromethane, then the organic phases are combined and washed with an aqueous solution, dried over magnesium sulphate, filtered and then concentrated. The product is then purified by chromatography on silica gel with a cyclohexane / ethyl acetate (80:20) eluent. The product is isolated with 31% yield in the form of a colorless oil. Characterization of 10a1 C36H37FO7 M = 600.67 g.mol- 'Rf = 0.45, eluent: cyclohexane / ethyl acetate (6: 4). 19F NMR (CDC13, 282.5 MHz) -205.4 (dd, JF_H = 47.3Hz and 7.5Hz) 25 1H NMR (CDC13, 300MHz) 20 - 39 -3.51 (dd, 11.4Hz and 1 , 7Hz, 1H, 1116); 3.63-3.77 (m, 3H, 1116, 112, H4); 3.88-3.97 (m, 2H, H5, H3); 4.39-4.9 (m, 8H, 4OCH Ph); 4.62 (d, 47.7Hz, 1H, CHF); 7.07-7.25 (m, 20H, Har); 9.74 (d, 7Hz, 1H, CHO). 13C NMR (CDCl3, 75.5MHz) 68.8 (C6); 73.0 (C5); 73.7 (OCH2Ph); 75.5 (OCH2Ph); 76.0 (OCH2Ph); 76.1 (OCH2Ph); 78.2 (C2); 78.4 (C4); 83.2 (C3); 91.1 (d, 175Hz, CHF); 128.0 -129.0 (Char.); 137.8; 138.3; 138.4; 138.7 (Char. Quat.); 200 (d, 30Hz, CHO). Mass (ESI +): 601 (M + H +); 618.27 (M: H2O hydrate); 636.27 (M: hydrate 2H2O).

Synthesis of compounds 10a2 Fi ure 14)

In a flask under an inert atmosphere at -78 C, containing the product 13a2 (0.165mmol; 1 eq.) In anhydrous tetrahydrofuran (3mL), a solution of 1M DIBAL-H in toluene (0.25mL, 0.25mmol, 1.5 eq.) Is added slowly. The medium is left under stirring at -78 ° C. for 4 hours. Then a saturated NH4Cl solution is added and the medium is brought to room temperature. After adding a solution of d (1M HCl, the medium is extracted three times with dichloromethane, then the organic phases are combined and washed with a saturated solution of NaHCO3, dried over magnesium sulphate, filtered and then concentrated. The product is then purified. by column chromatography on silica gel with a cyclohexane / ethyl acetate eluent (80:20). The product is isolated with 30% yield in the form of a colorless oil. Characterization of 10a2 C36H37FO7 M = 600.67 g .moF1 Rf = 0.6, eluent: cyclohexane / ethyl acetate (7: 3). 19F NMR (CDCl3, 282.5 MHz) -40- -211.1 (dd, JF_H = 47.2Hz and 7.5Hz) 1H NMR (CDCl3, 300MHz) 3.55-3.46 (m, 2H, H6); 3.8 (s, 1H, OH); 3.90 (dd, 9.7Hz and 2.7Hz, 1H, H3); 3.92 (s, 1H, 1-14); 4.06 (t, 9.6Hz, 1H, H5,); 4.12 (d, 9.6Hz, 1H, H2,); 4, 34 (d, 11.9Hz, 1H, OCH2Ph); 4.39 (d, 11.9Hz, 1H, OCH2Ph); 4.51 (d, 11.8Hz, 1H, OCH Ph); 4.52 (d, 10.6Hz, 1H, OCHPh); 4.57 (d, 11.6Hz, 1H, OCH2Ph); 4.59 (d, 47.6Hz, 1H, CHF); 4.67 (d, 1 1.5Hz, 1H, OCH2Ph); 4.85 (d, 11.8Hz, 1H, OCH Ph); 4.88 (d, 10.6Hz, 1H, OCH Ph); 7.30 (m, 20H, Har); 9.41 (d, 8.3Hz, 1H, CHO). 13C NMR (CDCl3, 75.5MHz) 68.8 (C6); 71.4 (C5); 72.7 (OCH2Ph); 73.9 (OCHzPh); 74.0 (C4); 74.5 (C2); 74.7 (OCH2Ph); 75.4 (OCHzPh); 81.1 (C3); 94.4 (d, 190.8Hz, CHF); 98.6 (d, 20Hz, Cl); 127.9; 128.0; 128.1; 128.2; 128.3; 128.4; 128.7; 128.8; 128.9; 129.0 (Char.); 137.8; 138.1; 138.3; 139.0 (quat. Char.); 195.5 (d, 28Hz, CHO). Mass (ESI +): 655.33 (M: OMe + Na hydrate).

Synthesis of compound lla1 (Figure 10)

In a flask under an inert atmosphere containing the ester 2a1 (52 mg; 0.08 mmol; 1 eq.) In solution in ethanol (5 ml) the NaBH4 (10 mg, 0.241 mmol, 3 eq.) Is added and the medium is left stirring for 12 hours. The mixture is concentrated and then taken up in a dichloromethane / water mixture, then after decantation, the aqueous phase is extracted three times with dichloromethane. The organic phases are then combined and washed with a saturated aqueous solution of NaCl (15 ml), dried over magnesium sulphate, filtered and then evaporated. The crude is then purified by chromatography column on silica gel with a cyclohexane / ethyl acetate (50:50) eluent. The product is isolated with 38% yield in the form of a colorless oil. - 41 Characterization of lla1 C36H39FO7 Rf: 0.53 (cyclohexane / ethyl acetate 5/5), 5 NMR 19F, (CDC13, 282.5 MHz) -199.2 (dt, JF_H = 46, lHz and 19, 3Hz) 1H NMR (CDCl3, 300MHz) 2.11 (s,, 1H, OH); 3.58-3.65 (m, 3H, H2 and 2H6); 3.81-4.00 (m, 5H, CL I2, 114, H5, H3); 4.44 (td, 3.7Hz & 46.5Hz, 1H, CHF); 4.48 -4.81 (m, 8H, 4 OCLI2Ph); 7.26 (m, 10M = 602.69 g.mol- '20H, Har.). 13C NMR (CDCl3, 75.5MHz) 60.4 (d, 24.6Hz, CH2); 68.8 (C6); 72.1 (C5); 73.6 (OCH2Ph); 75.2 (OCH2Ph); 75.9 (2C) (OCH2Ph); 78.1 (C2); 78.6 (C4); 83.3 (C3); 90.1 (d, 183Hz, CHF); 97.9 (d, 22Hz, Cl); 127.8; 127.9 (2C); 128.0; 128.1; 128.3; 128.6 (2C) (Char.); 137.8; 138.0 (2C); 138.4 (Çar. Quat.). Mass (ESI +): 625.33 (M + Na). Synthesis of compound llb2 (Figure 10) In a flask under an inert atmosphere containing ester 2122 (52mg; 0.08mmol; 1 eq.) 20 dissolved in ethanol (5 mL) NaBH4 (10mg, 0.241mmol, 3 eq.) Is added and the medium is left under stirring for 12 hours. The mixture is concentrated and then taken up in a dichloromethane / water mixture, then after decantation, the aqueous phase is extracted three times with dichloromethane. Then the organic phases are combined and washed with a saturated aqueous solution of NaCl (15mL), dried over magnesium sulfate, filtered and then evaporated. The crude is then purified by chromatography column on silica gel with a cyclohexane / ethyl acetate (50:50) eluent. The product is isolated with 42% yield in the form of a colorless oil. 15 -42 - Characterization of 111) 2 C36H39FO7 M = 602.69 g.mor 'Rf: 0.53 (cyclohexane / ethyl acetate 5/5), 19F NMR (CDCl3, 282.5 MHz) -209.7 (dddd, JF_H = 47.3Hz, 27Hz, 22.6Hz & 4.3Hz) 1H NMR (CDCl3, 300MHz) 2.26 (dd, 5.1Hz & 7Hz, 1H, OH); 3.44 (dd, 0.9Hz & 9.1Hz, 1H, H2); 3.50-3.67 (m, 5H, 2H6, CH2, H ~; 3.89-3.94 (ddd, 2.2Hz, 3.2Hz and 10Hz, 1H, Hf); 4.00 (t, 9.1Hz, 1H, H3); 4.36 (td, 3.7Hz and 46.5Hz, 1H, CHF); 4.38 (d, 12Hz, 1H, OCH2Ph); 4.47 (d, 12Hz, 1H , OCH2Ph); 4.48 (d, 10.9Hz, 1H, OCH2Ph); 4.63 (d, 11.2Hz, 1H, OCH2Ph); 4.74 (d, 11Hz, 1H, OCH2Ph); 4.82 (d, 10.1Hz, 1H, OCH2Ph); 4.86 (d, 11.2Hz, 1H, OCH2Ph); 7.09-7.12 (m, 20H, Har); 9.45 (d, 7, 4Hz, 1H, CHO).

13C NMR (CDCl3, 75.5MHz) 61.2 (d, 22Hz, CH2); 68.5 (C6); 71.8 (C5); 73.8 (OCH2Ph); 75.4 (OCH2Ph); 76.1 (OCH2Ph); 77.6 (OCH2Ph); 78.1 (C2 or C4); 79.2 (C2 or C4); 83.5 (C3); 93.2 (d, 179Hz, CHF); 97.6 (d, 20Hz, Cl); 128.1; 128.2 (2C); 128.3; 128.7; 128.8; 128.9; 129.0; 129.3 (Char.); 137.7; 138.3; 138.4; 138.7 (Char. Quat.).

Synthesis of copmose 12a1 Figure 12 In a flask under an inert atmosphere containing the alcohol II (34 mg; 0.056 mmol; 1 eq.) In solution in anhydrous dichloromethane (1 mL) at 0 C, triethylamine (10 L;: 25 0.075mmol ; 1.3eq.) And then slowly the MsCl (71.tL, 0.075mmol, 1.3 eq.) Are added. The medium is left under stirring at 0 C for 30 minutes, then at room temperature for 3 hours. The mixture is hydrolyzed, then extracted three times with dichloromethane. The organic phases are then combined and washed with saturated aqueous NaCl solution, dried over magnesium sulfate, filtered and then evaporated. The crude is then purified by chromatographic column on silica gel with a cyclohexane / ethyl acetate eluent (70:30). The product is isolated with 50% yield in the form of a white oil.

Characterization of 12a1 C37H41 FO9S M = 680.8 g.moYl Rf: 0.83 (cyclohexane / ethyl acetate 5/5), 19F NMR (CDC13, 282.5 MHz) -186.3 (ddd, JF_H = 51 , 5Hz, 35.4Hz & 18.2Hz) 1H NMR (CDCl3, 300MHz) 2.95 (s, 3H, CH3); 3.45 (dd, 5.6Hz & 9.1Hz, 1H, 1116); 3.55 (dd, 7.6Hz & 9.1Hz, 1H, 1H6); 3.98 (bs, 2H, H3, H4; 4.08 (t, 6.8Hz, 1H, Hf); 4.37 (1s, 3H, H2 and OCH Ph); 4.54 (d, 11.5Hz , 1H, OCH Ph); 4.67 (s, 2H, OCHzPh); 4.68 (d, 1H, OCH Ph); 4.73 (dd, 30Hz & 12.3Hz, 2H, CH2); 4.9 (d, 11.4Hz, OCH2Ph); 4.93 (d, 11.3Hz, 1H, OCI Ph); 4.97 (dd, 8.3Hz and 48Hz, 1H, CHF); 7.24 (m, 20H , Har) .13C NMR (CDCl3, 75.5MHz) 37.8 (CH3); 67.7 (C6); 68.3 (d, 21.7Hz, CH2); 73.1 (OCH2Ph); 73.6 (C4); 73.7 (OCH2Ph); 74.9 (d, 3.5Hz, C2); 75.0 (OCH2Ph); 75.1 (Cf); 75.7 (OCH2Ph); 80.3 (C ); 90.5 (d, 189.6Hz, CHF); 106.0 (d, 21.1Hz, Cl); 127.7; 127.8; 128.0; 128.1 (2C); 128.5 ; 128.6; 128.7 (2C) (Car.); 137.7; 137.9; 138.1; 138.5 (Car quat.) Mass (ESI +): 680 (M + H +); 716 (M: hydrate 2H2O). - 44 Synthesis of compounds 13a2 (Figure 13)

In a flask under an inert atmosphere at -0 C, containing 1M Me2AlCl in cyclohexane (1.5mL; 1.44mmol, 3 eq.) In dichloromethane (15mL), Weinreb amine (141mg; 1.44mmol; 3 eq.), then the mixture is stirred for lheure. The 2ag ester (311mg; 0.481mmol; leq.) In anhydrous dichloromethane (5mL) is added at 0 ° C., then the temperature of the solution is allowed to return to ambient temperature and with stirring for 12 hours. The reaction is hydrolyzed with a 1M HCl solution, filtered over Celite, dried over magnesium sulfate, then concentrated. The product is then purified by chromatographic column on silica gel with a cyclohexane / ethyl acetate (50:50) eluent. The product is isolated with 75% yield in the form of a yellow oil. Characterization of 1312 C38H42FO8 M = 659.76 g.morl Rf = 0.62, eluent: cyclohexane / ethyl acetate (5: 5). 19F NMR (CDCl3, 282.5 MHz) -196.8 (d, JF_H = 48.3Hz) 1H NMR (CDCl3, 300MHz) 3.1 (s, 3H, CH3); 3.44-3.57 (m, 2H, H6.); 3.59 (s, 3H, OCH3); 3.93 (s, 1H, H1); 4.00-4.04 (m, 2H, H2, H3); 4.15 (t, 9.6Hz, 1H, H5,); 4.37 (m, 2H, OCH2Ph); 4.53 (d, 11.5Hz, 1H, OCH2Ph); 4.64-4.78 (m, 3H, OCH2Ph); 4.84-4.94 (m, 2H, OCH2Ph); 5.14 (d, 48.2Hz, 1H, CHF); 7.21-7.29 (ni, 20H, Har). 13C NMR (CDCl3, 75.5MHz) 32.3 (CH3); 62.3 (OCH3); 68, (C6); 70.5 (C5); 73.4 (OCH2Ph); 73.7 (OCH2Ph); 75.0 (OCH2Ph); 75.2 (C4); 75.6 (OCH2Ph); 80.7 (C2 and C3); 127.9; 128.0; 128.2 5 - 45 - (2C); 128.6 (2C); 128.8; 128.9; 129.1 (Car.); 138.4, 138.7; 138.9; 139.4 (Çar. Quat.). Mass (ESI +): 660 (M + H); 677 (M + H2O) Synthesis of compounds 14a1 / 14a2 (Figure 15)

On a suspension of 2a1 / 212 acid (253 mg; 0.42 mmol; 1.0 eq.), Alanine (0.42 mmol; 1.0 eq.), HOBT (65 mg; 0.47 mmol; 1.1 eq.), and NMM (143 mg; 10 1.41 mmol; 3.3 eq.) in DMF (15 mL) under an argon atmosphere, EDCI (90 mg; 0.47 mmol; 1.1 eq.) is added after 15 minutes. The reaction is stirred at room temperature for 24 hours and concentrated. A 1N hydrochloric acid solution (10 mL) is added together with dichloromethane, and the aqueous phase is extracted with DCM (3 x 20 mL). The organic phases are washed with saturated NaCl solution (20 mL), dried over Mg504 and concentrated in vacuo. The residue is purified by chromatography on silica gel with a cyclohexane / AcOEt mixture (70:30) as eluent to allow the separation of the 2 diastereoisomers 14a1 and 14x2 in the form of 2 white solids with an overall yield of 60%. 20 Characterization of 14a1 /, 14x2 25 C46H48FNO9 M = 777.87g.mo1-1 Compound 14a1 30 Rf =, eluent: cyclohexane / ethyl acetate O. - 46 - 19F NMR, (CDCl3, 282.5 MHz) - 200 (d, JF_H = 47.3Hz) 1H NMR (CDCl3, 300MHz) 1.25 (d, 7.2Hz, 3H, CH3); 3.43 (dd, 5.6Hz & 9.4Hz, 1H, 1H6); 3.59 (dd, 7.6Hz & 9.4Hz, 1H, 1E16); 4.01 (s, 1H, H4); 4.11 (dd, 2.6Hz & 10Hz, 1H, H3); 4.19 (t, 6.3Hz, 1H, H5,); 4.24 (d, 10Hz, 1H, H2); 4.37 (d, 11.7Hz, 1H, OCH2Ph); 4.43 (d, 11.7Hz, 1H, OCHzPh); 4.62 (m, 1H, CHI; 4.66 (d, 11.7Hz, 1H, OCH2Ph); 4.71 (d, 11.3Hz, 1H, OCH2Ph); 4.76 (s, 2H, OCH Ph ); 4.56 (d, 11.7Hz, 1H, OCH2Ph); 4.99 (d, 47.7Hz, 1H, CHF); 5.00 (d, 11.3Hz, 1H, OCH Ph); 5, 19 (s, 2H, CO2CH Ph); 5.55 (s, 1H, OH); 7.07 (dd, 3.5Hz & 7.6Hz, 1H, NH); 7.21-7.29 (m, 25H, Har) .13C NMR (CDCl3, 75.5MHz) 18.3 (CH3); 48.1 (CH); 67.5 (CO2CH2Ph) 68.8 (C6); 70.6 (Cf); 72, 9 (OCH2Ph); 73.5 (OCH2Ph); 74.4 and 74.5 (C2 and C4); 74.6 (OÇH2Ph); 75.6 (OCH2Ph); 80.4 (Ci); 86.6 ( d, 201.8Hz, CFH); 98.1 (d, 20.7Hz, Cl); 127.6; 127.9; 128.3; 128.4; 128.5; 128.6; 128.8 ( Çar.); 135.2; 138.0; 138.1; 138.5; 138.9 (Quat Char); 168.9 (d, 19.6Hz, COCFH); 171.8 (ÇO). Mass (ESI +): 760.27 (M + H); 795.2 (M + H2O) Compound 14a2 Rf =, eluent: cyclohexane / ethyl acetate Q.

19F NMR (CDCl3, 282.5 MHz) - 201.9 (d, JF_H = 47.3Hz) 1H NMR (CDCl3, 300M: Hz) 1.23 (d, 7.0Hz, 3H, CH3); 3.49 (dd, 5.8Hz & 9.1Hz, 1H, 1H6); 3.56 (dd, 7.5Hz & 9.1Hz, 1H, 1116); 3.94 (s, 1H, H4); 4.0 (dd, 2.7Hz & 9.7Hz, 1H, H3); 4.12-4.23 (m, 2H, H5 and H2); 4.35 (d, 11.8Hz, 1H, OCH2Ph); 4.42 (d, 11.8Hz, 1H, OCH2Ph); 4.49-5.10 (m, 10H, CH; 4OCH2Ph; CHF); 7.09-7.24 (m, 25H, Har). 35 -47-Synthesis of compounds 15a, (Figure 16) In a flask, compound 14a1 (0.100 mmol) is dissolved in tetrahydrofuran (10 mL) with water (5mL) and palladium on charcoal and placed under a hydrogen atmosphere. The mixture is stirred for 2 days at room temperature. The reaction mixture is filtered, and concentrated. The crude is taken up in dichloromethane (20 mL) which is removed, then with water (10 mL) which is filtered. The aqueous phase is then concentrated to thereby leave the desired product as a pale yellow solid with a yield of 98%.

Characterization of 15a1 OH C11H18FN09 M = 327.26g.mo1-1 1H NMR (D20, 300MHz) 1.4 (d, 7.2Hz, 3H, CH3); 3.6-3.0 (m, H6, He, HD; 3.95 (s, H ~; 4 (m, H2 and H3); 4.05 (t, 1H, H5); 4.1-4 , 3 (m, Hb, He and Hd); 4.5 (m, 1H, CH); 5.1 (2d, 47Hz, CHF) 13C NMR (D3O, 75.5MHz) 15.0 (CH3); 47.4 (CH); 59.8 (C6); 65.9 (C4); 68.1 and 68.9 (C2 and C3); 70.9 (C5); 86.6 (d, 198Hz, CFH ); 96.4 (d, 20.7Hz, Cl); 170 (d, 19.6Hz, COCFH); 171.8 (CO). Mass (ESI +): 345.03 (M + Na) - 48 - Synthesis compounds 16a1 (Figure 17) On a suspension of acid 5a1 (253 mg; 0.42 mmol; 1.0 eq.), peptide (0.42 mmol; 1.0 eq.), HOBT (65 mg; 0.47 mmol; 1.1 eq. .), and of NMM (143 mg; 1.41 mmol; 3.3 eq.) in DMF (15 mL) under an argon atmosphere, EDCI (90 mg; 0.47 mmol; 1.1 eq.) is added after 15 minutes. The reaction is stirred at room temperature for 24 hours and concentrated. 1N hydrochloric acid solution (10 mL) is added together with dichloromethane, and the aqueous phase is extracted with DCM (3 x 20 mL). are washed with saturated NaCl solution (20 mL), dried over MgSO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel with a cyclohexane / AcOEt mixture (30:70) as eluent to isolate compound 16ai in the form of a white solid with an overall yield of 56%.

Characterization of 16a1 C63H70FN4O13 M = 1110.25g.mor1 Rf =, eluent: cyclohexane / ethyl acetate Q. 19F NMR (CDCl3, 282.5 MHz) - 199.4 (d, JF_H = 48.4Hz) 1H NMR ( CDCl3, 300MHz) 1.22 and 1.30 (2d, 7, Hz, 6H, 2CH3); 1.22-1.51 (m, 6H, 3CH lys); 3.01-3.07 (m, 1H, 1 CHZNH); 3.23-3.30 (m, 1H, 1 CHZNH) 3.37 (dd, 5.8Hz & 9.4Hz, 1H, 11-16); 3.47 (dd, 9.2Hz, 1H, 1H6); 4.01 (s, 1H, H4); 4.1 (dd, 1.8Hz & 10Hz, 1H, H3); 4.15-4.24 (m, 3H, H5, CHLys, H2); 4.45-4.73 (m, 6H, 2CHAla, OCHZPh); 4.77 (s, 2H, OCHZPh); 4.93-5.21 (m, 6H, OCH Ph); 5.01 (d, 47.2Hz, 1H, CHF); 5.51 (d, -49-6.9Hz, 1H, NH); 5.65 (s, 1H, OH); 6.49 (d, 7.4Hz, 1H, NH); 6.62 (d, 7.3Hz, 1H, NH); 6.73 (s, 1H, NH); 7.18-7.23 (m, 25H, Har). 13C NMR (CDCl3, 75.5MHz) 18.1 and 18.3 (2CH3); 22.3 (CH2); 28.7 (H2); 32.0 (CH2); 38.5 (NCH2); 48.3 and 48.9 (2CHA1a); 54.8 (CHLys); 67.1 (OCH2Ph); 67.2 (OCH2Ph); 68.5 (C6); 70.4 (Cf); 72.8 (OCH2Ph); 73.4 (OCH2Ph); 74.6 (C4 and C2); 74.7 (OCH2Ph); 75.5 (OCH2Ph); 80.3 (C3); 86.8 (d, 200.7Hz, CFH); 98.1 (d, 20.7Hz, Cl); 127.0; 127.6; 128.0; 128.2; 128.3 (2C); 128.4 (2C); 128.5; 128.6; 128.7 (Char.); 136.3; 138.0; 138.2; 138.3; 138.5; 138.7; 138.8; 138.9 (Char. Quat.); 156.0 (CO); 169.4 (d, 19Hz, COCFH); 171.7 and 172.6 (2CO). Mass (ESI +): 1128.33 (M + H20)

Synthesis of compounds 17a1 (Figure 18) In a flask, compound 16a1 (0.028 mmol) is dissolved in tetrahydrofuran (5 mL) with 1N hydrochloric acid solution (1.2 eq.) And palladium on charcoal and placed under a hydrogen atmosphere. The mixture is stirred for 2 days at room temperature. The reaction mixture is filtered, and concentrated. The crude is taken up in dichloromethane (20 mL) which is removed, then with water (10 mL) which is filtered. The aqueous phase is then concentrated to thus leave the desired product as a white solid with a quantitative yield Characterization of 17a: 25 C20H35C1FN4011 M = 561.96g.mol "1 19F NMR (CDCl3, 282.5 MHz) - 199.4 (d, JF_H = 48.4Hz) 1H NMR (CDCl3, 300MHz) 1.22 and 1.30 (2d, 7, Hz, 614, 2CH3); 1.22-1.51 (m, 6H, 3CH2lys); 3.01-3.07 (m, 1H, 1CH2NH); 3.23-3.30 (m, 1H, 1CH2NH) 3.37 (dd, 5.8Hz and 9.4Hz, 1H, 1E16 ); 3.47 6 OH OO HO v O \ ~ CN 1 NH OH 2 H HO'4 Ya "OH O = O NH3`CI- OH 17a1 - 50 - (dd, 9.2Hz, 1H, 1116); 4.01 (s, 1H, H4); 4.1 (dd, 1.8Hz & 10Hz, 1H, H3); 4.15-4.24 (m, 3H, H5, CHLys, H2); 4.45-4.73 (m, 6H, 2CHAla, OCH2Ph); 4.77 (s, 2H, OCH2Ph); 4.93-5.21 (m, 6H, OCH2Ph); 5.01 (d, 47.2Hz, 1H, CHF); 5.51 (d, 6.9Hz, 1H, NH); 5.65 (s, 1H, OH); 6.49 (d, 7.4Hz, 1H, NH); 6.62 (d, 7.3Hz, 1H, NH); 6.73 (s, 1H, NH); 7.18-7.23 (m, 25H, Har). 13C NMR (CDCl3, 75.5MHz) 18.1 and 18.3 (2CH3); 22.3 (CH2); 28.7 (CH2); 32.0 (CH2); 38.5 (NCH2); 48.3 and 48.9 (2CHAla); 54.8 (HLys); 67.1 (OCH2Ph); 67.2 (OCH2Ph); 68.5 (C6); 70.4 (C5); 72.8 (OCH2Ph); 73.4 (OCH2Ph); 74.6 (C4 and C2); 74.7 (OCH2Ph); 75.5 (OCH2Ph); 80.3 (C3); 86.8 (d, 200.7Hz, CFH); 98.1 (d, 20.7Hz, Cl); 127.0; 127.6; 128.0; 128.2; 128.3 (2C); 128.4 (2C); 128.5; 128.6; 128.7 (Char.); 136.3; 138.0; 138.2; 138.3; 138.5; 138.7; 138.8; 138.9 (Char. Quat.); 156.0 (CO); 169.4 (d, 19Hz, COCFH); 171.7 and 172.6 (2CO). Mass (ESI +): 1128.33 (M + H2O) Synthesis of compounds 18b1 (Figure 19)

On a suspension of acid 5b1 (500 mg; 0.811 mmol; 1.05 eq.), 4-aminophenol (84 mg; 0.773 mmol; 1.0 eq.), HOBT (110 mg; 0.811 mmol; 1.05 eq.), and NMM (800, mg; 0.811 mmol; 1.05 eq.) in DMF (20 mL) under an argon atmosphere, EDCI (156 mg; 0.811 mmol; 1.05 eq.) is added after 15 minutes. The reaction is stirred at room temperature for 24 hours and concentrated. A 1N hydrochloric acid solution (10 mL) is added together with dichloromethane, and the aqueous phase is extracted with DCM (3 x 20 mL). The organic phases are washed with saturated NaCl solution (20 mL), dried over MgSO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel with a cyclohexane / AcOEt (60:40) mixture as eluent in order to isolate the compound 18b1 in the form of a white solid with an overall yield of 44%. -51 - Characterization of 18b1 C42H41FNO8 M = 706.78g.mol "1 Rf = 0.27 eluent: cyclohexane / ethyl acetate (7/3).

19F NMR (CDCl3, 282.5 MHz) - 197.6 (d, JF_H = 47Hz) 1H NMR (CDCl3, 300MHz) 3.53 (dd, 11.3Hz, 1H, 1H6); 3.55-3.71 (m, 3H, 1H6, H4, H2); 3.98 (m, 1H, H5); 4.1 (t, 9.4Hz, 1H, H3); 4.36 (d, 12.2Hz, 1H, OCH, Ph); 4.42 (d, 12.4Hz, 1H, OCH2Ph); 4.53 (d, 10.9Hz, 1H, OCH Ph); 4.64 (d, 11.5Hz, 1H, OCH Ph); 4.79 (d, 10.9Hz, 1H, OCH2Ph); 4.86 (s, 2H, OCH2Ph); 4.92 (d, 11.4Hz, 11-1, OCH Ph); 4.95 (d, 48Hz, 1H, CHF); 5.46 (s, 1H, OH); 6.7 (d, 8.8Hz, 2H, Har.); 7.13-7.25 (m, 22H, Har); 7.86 (d, 5.5Hz, 1H, NH) ;. 13C NMR (CDCl3, 75.5MHz) 68.8 (C6); 72.4 (C5); 73.7 (OCH2Ph); 75.4 (OCH2Ph); 75.8 (OCH2Ph); 76.2 (OCH2Ph); 78.3 (C2); 78.6 (C4); 83.3 (C); 87.1 (d, 202Hz, CFH); 98.0 (d, 20Hz, Cl); 116.2 (2Car.); 123, 1 (2Car.); 127.9-129.1 (Char.); 138.2; 138.5 (2C); 138.8 (Quat Char); 153.9 (Char.OH); 167.5 (d, 18Hz, COCFH). Mass (ESI +): 730.2 (M + 23) Synthesis of compounds 19b1 / 19b2 (Figure 20) On a suspension of 9b1 / 9b2 acid (253 mg; 0.42 mmol; 1.0 eq.), Peptide (240 mg ; 0.42 mmol; 1.0 eq.), HOBT (65 mg; 0.47 mmol; 1.1 eq.), And NMM (143 mg; 1.41 mmol; 3.3 eq.) In DMF (15 mL) under argon atmosphere , EDCI (90 mg; 0.47 mmol; 1.1 eq.) is added after 15 minutes. The reaction is stirred at room temperature for 4 days and concentrated. A 1N hydrochloric acid solution (10 mL) is added together with dichloromethane, and the aqueous phase is extracted with DCM (3 x 20 mL). The organic phases are washed with saturated NaCl solution (20 mL), dried over MgSO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel with a cyclohexane / AcOEt (1: 1) mixture as eluent to allow separation of the 2 diastereoisomers in the form of 2 white solids with an overall yield of 64%. C60H66FN3011 Characterization of 19b1 Rf = 0.52, eluent: cyclohexane / ethyl acetate (1: 1). 19F NMR (CDCl3, 282MHz) -197.6 (dd, 1JF-H7 '46.1, 24-H1' 19.3) 1H NMR (CDCl3, 300MHz) 1.26-1.68 (9H, m, H3, H4, H5, CH3), 2.82- 2.89 (1H, m, H2), 3.11-3.19 (1H, m, H2), 3.61 (1H, t, 3J 9.7), 3.71 (3H, sapp, 2H6 '), 3.88-3.94 (2H, m), 4.10 -4.15 (1H, m, H6), 4.49-4.63 (6H, m, H9), 4.78-5.24 (7H, m, H7 '), 5.50 (1H, d, 3JH12-H6 7.9, H12), 6.38 (1H , d, 3JH1-H22.7, Hl), 6.74 (1H, d, 3JH8-H97.1, H8), 7.12-7.33 (30H, m, Hqr), 13C NMR (CDCl3 M, 75Hz) 18.1 (C11) , 22.3 (C4), 27.9 (C3), 32.1 (CS), 38. 4 (C2), 48.3 (C9), 54.6 (C6), 67.0, 67.3, 69.1, 73.5, 74.6, 75.2, 75.6, 78.2, 77.4 (d, 3JC2'-F 7.4, C2 '), 79.0 (d, 2JC1 ^ _F 20.0, Cr, 79.4, 87.3, 90.8 (d, 1JC7'_F 191.3, C7'), 127.1, 127.3, 127.6, 127.7, 127.8 , 127.8, 127.9, 128.0, 128.0, 128.1, 128.1, 128.2, 128.3, 128.5, 128.5, 128.6, 128.6, 128.7, 128.7, 135.4, 136.4, 138.1, 138.3, 138.4, 138.5, 156.3, 167.2 (d, 2JC8'- F 19.4, CS), 174.2, 172.6, 171.4. M = 1024.21 g.moF1 - 53 - Characterization of 1913 2 Rf = 0.43, eluent: cyclohexane / ethyl acetate hyl (1: 1). 19F NMR (CDCl3, 282MHz) -206.2 (dd, 1JF_H7 '47.2, 2JF-H1' 29.0) 1H NMR (CDCl3, 300MHz) 1.68-1.26 (9H, m, CH3, 2H4, 2H5, 2H3), 3.28-3.11 ( 211, m, 2H2), 3.73-3.62 (3H, ni), 3.94-3.88 (2H, m), 4.65-4.46 (6H, m, H9), 5.24-4.72 (7H, m, H7 '), 5.73 ( 1H, d, 3J 7.6), 6.69 (1H, d, 3J 6.9), 6.80 (1H, Sapp), 7.33-7.12 (30H, m, HAr), Synthesis of compounds 20b1 (Figure 21) In a flask, the compound 19b1 (30 mg; 0.028 mmol) is dissolved in tetrahydrofuran (5 mL) with 1N hydrochloric acid solution (1.2 eq.) And palladium on carbon and placed under a hydrogen atmosphere. The mixture is stirred for 2 days at room temperature. The reaction mixture is filtered, and concentrated. The crude is taken up in dichloromethane (20 mL) which is removed, then with water (10 mL) which is filtered. The aqueous phase is then concentrated to thereby leave the desired product as a white solid with a yield of 77%.

Characterization of 20b1 HF 6 'O ,,, - .. ~ OH i H 1 3 l0 HO 5' 8 'N4 N88 \ 11 HO 4' 2 'OH 2 6 O. ~ 7O OH NH3 + Cl 12 C17H30C1FN309 M = 439, 44g.mo1- 1 19F NMR (D20, 282MHz) -209.9 (IF, dd, 3JF-H 1 '29.0, 2JF-H7' 46.1) 1H NMR (D20, 300MHz) 1.34 (3H, d, 3JH114H9 7.1, CH3) , 1.42-1.47 (2H, m, 2H4), 1.50-1.58 (2H, m, 2H), 30 1.82-1.91 (2H, m, 2H5), 3.26-3.36 (4H, m, 2H2), 3.52-3, 80 (3H, m, 2116 ', H2'), 3.95 (1H, t, 3JH6-H56.5, H6), 4.15 (1H, q, 3JH9-H11 7.1, H9), 5.27 (1H, d, 2JH7 ' _F46.6, 1-17 ') 20bl - 54 - 13C NMR (D20, 75MHz) 17.3 (C11), 21.6 (CI), 28.2 (C3), 30.7 (Cf), 39.0 (C2), 53.4 (C6), 60.8 (C6 '), 68.7 (d, 3Jc2'_F 5.1, Cr), 77.5, 69.7, 78.4 (d, 2Jc1'_F 18.1, C1'), 80.3, 88.5 (d, 1JC7 ^ _F 191.8, CT), 169.2 (C10).

Mass spectrometry: ESI +: 440 (MH) +, 422 (MH-F120) +

Synthesis of compounds 201) 2 (Figure 21) In a flask, compound 11 (35 mg; 0.032 mmol) is dissolved in tetrahydrofuran (10 mL) with 1N hydrochloric acid solution (1.2 eq.) And palladium on charcoal and placed under an atmosphere of hydrogen. The mixture is stirred for 2 days at room temperature. The reaction mixture is filtered, and concentrated. The crude is taken up in dichloromethane (20 mL) which is removed, then with water (10 mL) which is filtered. The aqueous phase is then concentrated to thereby leave the desired product as a white solid with a yield of 75%. Characterization of 201) 2 H 6 'H F OOH H HO ~ .O 3 10 7 5' 1 om / \ 411 8 '1 HO. 4 '2' OH 2 OH 0 5 NH3 + Cl 201) 2 12

C17H30C1FN3O9 M = 439.44g.mo1- '20 NMR 19F (D20, 282MHz) -203.4 (1F, dd, 3JF_H1' 25.8, 2JF_H7 '48.3) NMR' H (D2O, 300MHz) 1.33 (3H, d, 3JH11_H9 7.1, Hl.), 1.42-1.32 (2H, m, H4), 1.58-1.51 (2H, m, H3), 1.88-1.82 (2H, m, H5), 3.31-3.21 (2H, m, H2), 3.49- 3.43 (2H, m), 3.64-3.58 (2H, m, H2 ', 25 H6'), 3.95-3.80 (3H, m, H6, H1 ', H6'), 4.15 (1H, q, 3JH9-H11 7.1 , H9), 5.20 (1H, d, 2JH7'-F 47.7, H7, 13C NMR (DAO, 75MHz) -55- 17.2 (C U.), 21. 6 (C4), 28.1 (C3), 30.8 (C5 ), 38.8 (C2), 52.0 (C9), 53.4 (C6), 61.4 (C6 '), 68.9 (d, 3JC2'-F 7.0, Cr, 77.7, 69.9, 78.9 (d, 2JCr_F 19.1, Cl'), 80.4, 90.6 (d, 'JC7'_F 190.9, Cr), 169.3 (C10).

Synthesis of compound 21b2 (Figure 22)

In a balloon under an inert atmosphere containing aldehyde 10! (130mg; 0.216mmol; 1 eq.) In solution in anhydrous THF (4 mL), triethylphosphonoacetate (86 L, 0.433mmol, 2 eq.), LiBr (38mg, 0.433mmo1, 2 eq.) And triethylamine (61 L, 0.433mmol, 2 eq.) Are added and the medium is left under stirring for 12 hours. The mixture is hydrolyzed (20mL of water), then extracted with ethyl acetate (3 * 15mL). Then the organic phases are combined and washed with water (15mL), then a saturated solution of NaCl (15mL), dried over magnesium sulphate, filtered and then evaporated. The crude is then purified by chromatographic column on silica gel with a cyclohexane / ethyl acetate (80:20) eluent. The product is isolated with 32% yield in the form of a colorless oil. Characterization of 211) 2 C40H43FO8 M = 670.76 g.mol-1 20 19F NMR (CDC13, 282.5 MHz) -200.4 (dd, JF_H = 19.4Hz and 47.3Hz) 1H NMR (CDC13, 300MHz ) 1.2 (t, 7.2Hz, 3H, CH3); 3.45 (d, 1H, OH); 3.5 (d, 9Hz, 1H, H2); 3.65 (t, 9.4Hz, 1H, H4); 3.60-3.75 (m, 2H, H6); 3.95 (m, 1H, H5); 4 (t, 10.5Hz, 1H, H3); 4.07 (qdt, 7.2Hz, 2H, CL I2); 4.47 (d, 12.3Hz, 1H, OCH, 22Ph); 4.55 (d, 12.2Hz, 1H, OCH1Ph); 4.58 (d, 10.7Hz, 1H, OC Ph); 4.60 (d, 11.1Hz, 1H, OCHPh); 4.76 (d, 11.5Hz, 1H, - 56 - OCM2Ph); 4.8 (d, 11.511z, 1H, OCM2Ph); 4.83 (d, 10.1Hz, 1H, OCH Ph); 4.90 (d, 10.9Hz, 1H, OCM2Ph); 4.97 (ddd, 1.7Hz, 5.9Hz & 46Hz, 1H, CHF); 5.86 (dt, 1.7Hz & 15.7Hz, 1H, H); 6.76 (ddd, 4.8Hz, 15.7Hz & 20Hz, 1H, CHF); 7.3 (m, 20H, Mar.).

13C NMR (CDCl3, 75.5MHz) 14.5 (CH3); 61.1 (CH2); 68.7 (C6.); 72.6 (C5); 73.8 (OCH2Ph); 75.1 (OCH2Ph); 75.4 (OCH2Ph); 76.0 ((OCH2Ph); 78.3 (C4); 78.5 (C2); 84.0 (C3); 92.7 (d, 181Hz, CHF); 97.5 (d, 20Hz, Cl) ; 124.2 (d, 11.6Hz, CH =); 128.0; 128.3; 128.6; 128.8 (2C); 128.9; 129.0 (Char.); 137.7; 138.4; 138.7 (2C) (Char. Quat.), 165.8 (ÇO) Synthesis of compounds 22a1 / 242 and 23 (Figure 23) In a flask under an inert atmosphere containing a mixture of acids 5a1 / 5a2 (120 mg; 0.195 mmol; 1 eq.), And N-methylmorpholine NMM (64 L; 65.6 mmol; 3 eq.) In DMF (5 mL), EDCI (41 mg; 0.214 mmol; 1 , 1 eq.) Is added. Stirring is maintained for 24 hours, then the solvent is evaporated off. The medium is taken up in dichloromethane and washed twice with a 1M HCl solution. The organic phase is dried over sodium sulfate. magnesium, filtered and concentrated. The crude is then purified on a chromatographic column and the two isomers of the compounds are isolated with a 9/1 cyclohexane / ethyl acetate mixture and a yield of 35%, the secondary compounds are isolated with a cyclohexa mixture. ne / ethyl acetate and a yield of 10% .25 - 57 - Characterization of 22a1 / 2 a2 C35H35FO5 M = 554.65 g.mol-1 5 19F NMR (CDC1 282.5MHz) -165.0 (d, 81Hz, 1F) - * 41% -159.1 (d, 77Hz, 1F) - * 59% 1H NMR (CDCl3, 300MHz) 3.63-3.76 (m, 3H, 2H6 and H3); 3.98 (td, 2.8 & 6Hz, 111, 115); 4.05 (t, 2.8Hz, 1H, H4); 4.14 (dd, 1.8 & 7.6Hz, 1H, H2); 4.40-4.81 (m, 8H, 4OCH Ph); 6.43 (dd, 1.4 & 77Hz, 1H, CHFmajo); 6.87 (d, 89Hz, 1H, CHFmino); 7.23 (m, 20H, Har) 13C NMR (CDCl 13.75.5MHz) 68.5 (M) and 69.1 (m) (2C6); 73.2 (OCH2Ph); 73.3 (OCH2Ph); 73.9 (OCH2Ph); 74.2 (C2 and C4); 74.3 (OCH2Ph); 79.1 (C5); 81.1 (C3); 128.0-128.9 (Char.); 15,138.1; 138.4; 138.6 (2C) (Quat Char.).

Characterization of 23 20 C35H37FO6 M = 572.66 g.mol-1 19F NMR (CDC13, 282.5MHz) -230.3 (t, 47Hz, 1F) 1H NMR (CDCl3, 300MHz) - 58 - 3.63-3 , 73 (m, 4H including 2E16); 3.90-3.96 (m, 2H); 4.2 (d, 47.3Hz, 1H, CHEF); 4.46 (d, 12.3Hz, 1H, OCLI2Ph); 4.52 (d, 10.8Hz, 1H, OCHLPh); 4.57 (d, 12.2Hz, 1H, OCH-Ph); 4.6 (d, 11Hz, 1H, OCH2Ph); 4.74 (d, 10.8Hz, 1H, OCLI2Ph); 4.80 (d, 11.1Hz, 1H, OCH Ph); 4.84 (d, 11.1Hz, 1H, OCLI2Ph); 4.86 (d, 11Hz, 1H, OCLI2Ph); 7.08-7.02 (m, 20H, Har) 13C NMR (CDCl13.75.5MHz) 68.8 (C6); 72.5 (C5 or C2) 73.9 (OCH2Ph); 75.3 (OCH2Ph); 75.9 (OCH2Ph); 76.1 (OCH2Ph); 78.3 (C5 or C2); 78.6 (C4); 83.6 (C3); 83.9 (d, 179Hz, CFH2); 96.6 (d, 19Hz, Cl); 128.0-128.9 (Char.); 137.8; 138.4; 138.6; 138.8 (Char. Quat.).

Synthesis of compounds 24b1 / 24b (Figure 24)

In a flask under an inert atmosphere containing triphenylphosphine (230mg; 0.88mmol; 1.2eq.), Tribromofluoromethane CFBr3 (86 L; 0.88mmol; 1.2eq.) And lactone lb (394 mg; 0.731 mmol; 1 eq.) in anhydrous THF, a solution of 1M diethylzinc Et2Zn in hexane or toluene (880 L; 0.88mmol, 1.2eq.) is added slowly dropwise. The mixture is stirred for 4 hours, then MeOH is added and the reaction medium is concentrated.The crude is then purified on a chromatographic column and the two isomers of the compounds are collected together with a 95/5 cyclohexane / ethyl acetate mixture and a 25% yield.

Characterization of 24b1 / 24b2 C35H34BrFO5 M = 633.54 g.mol "'Rf = 0.67, eluent: cyclohexane / ethyl acetate (8: 2). BnO 2 BnOe 4' OBn 24b1 / 24b2 OBn 2900406 -59- RMN- 19F (CDCl3, 282.5MHz) -99.0 (s, IF) -118.6 (s, IF) 1H NMR (CDCl3, 300MHz) 5 3.63-3.7 (m, 3H including 2E16); 3 , 80-3.85 (m, 1H); 4.18 (td, 0.5H); 4.29-4.63 (m, 9.5H); 7.10-7.24 (m, 20H, Har) Test in the presence of Glycosidase 10 To demonstrate the resistance of our compounds to glycosidases and thus prove their stability, compound 17a was engaged in reactions with galactosidases. It is in fact known that the following compounds undergo enzymatic degradations (figure 25).

The protocol used is as follows (figure 26) A solution of compound 17a1 (17.72 mg) in water (500 L) is added to a solution of phosphate buffer (0.07M; pH7, 4mL) containing a- galactosidase (5 units) and (3-galactosidase (6.25 units) at 37 C. The reaction is followed by 19F NMR NMR Samples are taken at 24 hours, then 48, 72, 96 and 120 hours.

No change is observed and the starting material is found.

Claims (18)

Claims 1. C-glycoside compound of formula I: CFY X where n is an integer equal to 1 or 2, Y represents a hydrogen atom or a chlorine atom or a bromine, X is a hydrogen atom or a chain linear or branched alkyl having at least one amine, amide, acid, ester, carbonyl, alcohol, aryl or a carbonyl, ester, amide, amine, alcohol, R group which are identical or different, represent an OH or OR 'group where R' is a linear or branched alkyl, benzyl, benzoyl, acetyl, pivaloyl, trialkylsilyl, tertiobutyldiphenylsilyl group or one or more sugars, RI represents OR ', NR "R"', N3, or a phthalimide R "and R" ', identical or different, represent a hydrogen atom or a linear or branched alkyl group, aryl, benzyl, benzoyl, acetyl, alkyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, R2 represents a hydrogen atom or a halogen or an OH, OR, NR group "R" 'or N3, as well as its derivatives in the form of the base, of addition salt with an acid physiologically or pharmaceutically acceptable inorganic or organic, hydrate or solvate. 2. Compound according to claim 1, characterized in that the linear or branched alkyl groups are groups having from 1 to 15 carbon atoms. 3. Process for the preparation of a compound of formula I according to claim 1, characterized in that, when Y represents a hydrogen molecule, it comprises a Reformatsky addition reaction of an alkyl bromofluoroacetate in the presence of zinc on the lactones of formula II: with n, R, R 'as defined in claim 1. 4. A method of manufacturing compounds of formula I according to claim 3, characterized in that it comprises a step of obtaining a compound of formula I in which X and Y are hydrogen atoms and R2 represents a hydroxyl. (OH) by reaction of a compound of formula I in which R2 = OH, Y = H and X = CO2H in the presence of a peptide coupling agent such as 3-ethyl-1 (N, N-dimethylaminopropylcarbodiimide (EDCI ) or dicyclohexyl carbodiimide (DCC) in the presence of a tertiary amine such as N-methylmorpholine (NMM) or diisopropylethylamine (DIEA). 5. Process for the manufacture of compounds of formula I in which Y represents a hydrogen molecule, characterized in that it comprises a reaction of an alkyl dibromofluoroacete in the presence of diethylzinc and triphenylphosphine on lactones of formula II. 6. Process for the manufacture of compounds of formula I in which Y represents a halogen atom such as chlorine and bromine, - 62 -characterized in that it comprises a reaction of alkyl dihalofluoroacete in the presence of diethylzinc on lactones of formula II. 7. Method according to one of claims 4 to 6, characterized in that the aforesaid lactones are obtained by steps of protection by benzylation of the sugar, followed by the acid hydrolysis of the anomeric position, then its oxidation. 8. Method according to one of claims 3 to 7, characterized in that compounds of general structure I with R2 = OH are halogenated to obtain compounds of general structure I with R2 = Cl or Br then reduced to obtain compounds of general structure I with R2 = H. 9. A C-glycoside compound of formula III obtained by the process according to claim 5: with n, R, R ', R2, X as defined in claim 1. 10. The method of claim 9 for the production of compounds of formula III in which X = Br, characterized in that it comprises a reaction of a lactone of formula II in the presence of tribromofluoromethane (CFBr3), triphenylphosphine and diethylzinc , compounds of formula III in which X = H are obtained by reacting a compound of formula I in which X = CO2H, R2 = OH and Y = H is reacted in the presence of a peptide coupling agent such as 3-ethyl-1 (N, N-dimethylaminopropylcarbodiimide (EDCI) or dicyclohexyl carbodiimide (DCC) in the presence of a tertiary amine such as N-methylmorpholine (NMM) or diisopropylethylamine (DIEA). 11. A compound of general formula III according to claim 9 wherein the double bond is reduced to obtain compounds of general formula I with R2 = H and Y = H. 12. Compound according to claim 1, characterized in that it has the following formula IV: where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or an OH group, OR, and obtained from the ester (X = CO2Et in formula I), either by reduction with diisobutylaluminum hydride or by reduction to alcohol (formula V) followed by oxidation. 13. Compound according to claim 1, characterized in that it has the following formula I: where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or an OH group, OR 20- 64 - Z represents an OH, OR3 with R3 = alkyl, benzyl, mesyl, tosyl, triflate or a halogen such as Cl, Br, I. 14. Compound according to claim 1, characterized in that it has the following formula VI: COR "" where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or a group OH, OR Z1 represents an H or NR "R" 'with R "and R', identical or different, represent a hydrogen atom or a linear or branched alkyl, aryl, benzyl, benzoyl, acetyl, alkyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyle, R 'represent OR "or NR" R "' or an amino acid obtained by reaction of the Wittig-Wadsworth-Horner-Emmonth type of a phosphonate on the aldehyde of formula IV. 15. Compound according to claim 1, characterized in that it has the following formula VII: COR "" where n is an integer equal to 2, - 65 - Y represents a hydrogen atom, R2 represents a hydrogen atom or an OH group, OR Z1 represents an H or NR "R" 'with R "and R', identical or different, represent a hydrogen atom or a linear or branched alkyl, aryl, benzyl, benzoyl, acetyl, alkyloxycarbonyl group , allyloxycarbonyl, benzyloxycarbonyl, R "" represent OR "or NR" R "'or an amino acid obtained by reduction of the double bond of formula VI. 16. Compound according to claim 1, characterized in that it has the following formula VIII: where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or an OH, OR group. , and obtained from the ester (X = CO2Et in formula 1), by saponification to acid (X = CO2H in formula I) by the action of lalithine or soda or potash, followed by coupling peptide with AA: an amino acid or a peptide, that is to say a chain of amino acids in the presence of conventional coupling agents such as dicycohexylcarbodiimide (DCC), 3-ethyl-l (N, N- dimethylaminopropylcarbodiimide (EDCI), (2- (7-Aza-1H benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate) (HATU), (2-1H benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (HBTU) with or without hydroxybenzotriazole (HOBt), and a tertiary amine such as N-methylmorpholine (NMM) or diisopropylethylamine (DIEA) or triethylamine (Et3N) .- 66 - 17. Compound according to claim 1, characterized in that it has the following formula IX: where n is an integer equal to 2, Y represents a hydrogen atom, R2 represents a hydrogen atom or an OH, OR group. , R4 represents hydrogen, halogen, NR "R ', OH or OR" with R "and R"', identical or different, represent a hydrogen atom or a linear or branched alkyl, aryl, benzyl, benzoyl, acetyl group , alkyloxycarbonyle, allyloxycarbonyle, benzyloxycarbonyle, or obtained from the ester (X = CO2Et in formula I), by saponification to acid (X = CO2H in formula I) by the action of lalithine or soda or potash , followed by coupling with an aromatic amine in the presence of conventional coupling agents such as DCC, EDCI, HATU, HBTU) with or without HOBT, and of a tertiary amine such as NMM, DIEA, Et3N. 18. C-glycoside compound of formula I according to claim 1, characterized in that the C-glycoside compound of formula I in which the radical R2 consists of an OH group occurring, when it is in solution in polar solvents and protics, in the various conventional forms of sugars in solution, namely: open forms, furanose and pyranose.