FR2941697A1 - New tagitinine derivatives are proteosome inhibitors useful for the treatment of cancer - Google Patents

Abstract

Tagitinine derivatives (I) and their salts, isomers and mixtures of isomers in all proportions, preferably mixture of enantiomers, including a racemic mixture, are new. Tagitinine derivatives of formula (I) and their salts, isomers and mixtures of isomers in all proportions, preferably mixture of enantiomers, including a racemic mixture, are new. Dotted line : absent or single bond; dotted line with bond : single bond or double bond; A 1>C-H, C-OR 4>, C-SR 5>or CNR 15>R 16>, preferably C-OR 4>or C-SR 5>(when the dotted line with bond is single bond) or C (when the dotted line with bond is double bond); A 2>C (when the dotted line is single bond) or C-H, C-OR 6>, or C-SR 17>, preferably COR 6>(when the dotted line is absent); A 3>C=CH 2or CH-CH 2R 7>; R : CH 3, CH 2F, CF 3, CHF 2, CHO, CH 2OH, CH 2OR 8>, CH 2OCOR 8>or CH 2OC(O)NR 8>, preferably CH 3; either R 1>H (when the dotted line with bond between 1C and 2C is double bond) or H, OR 9>, SR 10>, or NR 11>R 12>(when the dotted line with bond between 1C and 2C is single bond); or R 1>R 6>a bond between C and O which forms an epoxide between 1C and 10C; either R 2>H or OR 13>; or R 2>R 6>a bond between C and O which forms an epoxide between 14C and 10C; R 3>-X-R 14>; X : CO, CON or bond; R 4>H or 1-6C alkyl optionally substituted by one or more halo; R 5>1-6C alkyl optionally substituted by OH or 1-6C alkoxy; either R 6>H, 1-6C alkyl (optionally substituted by one or more halo), aryl-1-6C-alkyl, or benzyloxy-1-6C alkyl (both optionally substituted by 1-6C alkoxy), -CO-1-6C alkyl or SiRaaRbbRcc; or R 1>R 6>a bond between the carbon atoms and oxygen which forms an epoxide ring between 1C and 10C; or R 2>R 6>a bond between the carbon atoms and oxygen which forms an epoxide ring between 14C and 10C; or R 14>R 6>group of formula ((CH 2) n-O-(CH 2) m); m, n : 1-3, preferably 1; R 7>H, OR 18>, SR 19>, or NR 20>R 21>, preferably OR 18>, SR 19>, or NR 20>R 21>; R 8>1-6C alkyl optionally substituted by one or more halo; R 18>, R 9>H, 1-6C alkyl (optionally substituted by one or more halo or OH), 1-6C alkoxy, aryl or -O-CO-1-6C alkyl; R 10>, R 17>, R 19>1-6C alkyl (optionally substituted by OH), 1-6C alkoxy or -O-CO-1-6C alkyl; either R 11>, R 12>H, OH, 1-6C alkyl, or aryl-1-6C alkyl, where R 11>and R 12>cannot represent OH at the same time; or NR 11>R 12>5 or 6 membered heterocycle optionally comprising one or more heteroatoms comprising O, S or N and optionally substituted by 1-6C alkyl; R 13>H, O-protecting group, 1-6C alkyl, CO-1-6C alkyl, SiRaaRbbRcc or -SO 2CF 3; R 14>benzyloxy1-6C alkyl, aryl or heteroaryl (all optionally substituted by one or more halo, 1-6C alkoxy, aryl or NR 22>R 33>), 1-6C alkyl, 1-6C epoxyalkyl, 2-6C alkenyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-6C alkyl, 5-10C polycycloalkyl, or aryl-1-6C alkyl; either R 15>, R 16>H, OH, 1-6C alkyl or aryl-1-6C alkyl, where R 15>and R 16>are not OH at the same time; or NR 15>R 16>5 or 6 membered heterocycle optionally comprising one or more heteroatoms comprising O, S or N and optionally substituted by 1-6C alkyl; either R 20>, R 21>H, OH, 1-6C alkyl or aryl-(1-6C) alkyl, where the R 20>and R 21>can not represent OH at the same time; or NR 20>R 21>5 or 6-membered heterocyclic ring, optionally containing, in addition to the nitrogen atom, one or more heteroatoms comprising O, S or N, and optionally substituted by 1-6C alkyl; R 22>, R 23>H or 1-6C alkyl; and Raa, Rbb, Rcc : 1-6C alkyl. Provided that (I) excludes: tagitinine C and tagitinine F; compound (in which A 2>-O is (C-O) (where the dotted line is single bond), the dotted line with bond is single bond, A 1>is C-OH or C-OCH 3, A 3>is CH=CH 2, R is CH 3, R 1>is OCH 3or OH, R 2>is H and R 3>is -COCH(CH 3) 2or -COCCH 3=CHCH 3); and compound (in which the dotted line is absent, (A 1>=O is C=O) the dotted line with bond between 1C and 2C is double bond, A 3>is CH=CH 2, R 1>and R 2>is H is OCH 3or OH, R is CH 3(R 3>is -COCH(CH 3) 2or -COCCH 3=CHCH 3) or CH 2OH (R 3>is -C(=O)-CCH 3=CH-CH 3)). Independent claims are included for: (1) the preparations of (I); (2) a composition comprising (I) in combination with a vehicle; (3) substituted tagitinine derivatives (III) of formula (IIIa) or (IIIb); and (4) preparation of (IIIa) (where R 1>is H, dotted line is single bond) from tagitinine C comprising: (a) optionally protecting the enone function in position 3 and/or protection of the double bond in C=CH 2position 11-13; (b) hydrolyzing isopropyl ester in position 8 to give the corresponding alcohol; (c) optionally deprotecting the enone function in position 3 and/or deprotection of the double bond in positions 11-13; and (d) isolating (IIIa) or (IIIb). R 1>H (when dotted line with bond is double bond) or OR 9>, SR 10>or NR 11>R 12>(when dotted line with bond is single bond); A 5>(C=O), CH-OH or CH-OGP1; GP1 : O-protecting group such as SiRaaRbbRcc; A 6>(C=CH 2) or CH-CH 2GP2; GP2 : a protective group of activated bonds such as imidazolyl or morpholinyl moiety; A 7>H, OH or OGP3; GP3 : O-protective group such as 1-6C alkyl or SiRddReeRff; and Rdd, Ree, Rff : 1-6C alkyl. [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Proteosome inhibitor.

Description

The present invention relates to derivatives of tagitinin C and tagitinin F, as well as their use, especially in the treatment of cancer.

Tagitinin C (TC) is a germacranolide extracted from Tithonia diversifolia, an Asteraceae rich in sesquiterpene lactones, which has varied biological activities including anti-proliferative activity on various cancer cells (Pal et al., J. Pharm Sciences 1976, 65, 918-920, Gu et al., J. Nat Prod 2002, 65, 532-536, Kuroda et al., Chem Pharm Bull 2007, 55, 1240-1244). Tagitin C is therefore part of the family of 15 following molecules isolated from Tithonia diversifolia (Pal et al., J. Pharm Sciences 1976, 65, 918-920, Pal et al., Indian J. Chem 1976, 14B, 77-89, Pal et al., Indian J. Chem., 1976, 14B, 259-262, Pal et al., Indian J. Chem., 1977, 15B, 208-211, Pal et al., Indian J. Chem. 1977, 15B, 533-535, Baruah et al., J. Org Chem 1979, 44, 1831-1835, Sarma et al., Phytochemistry 1987, 26, 2406-2407). Tagitinine A Tagitinine B 18 19 Tagitinine C 8 9 o Tagitinine D o Tagitinine E o Tagitinine F Tagitinin C is a non-catalytic proteasome inhibitor. In the cell, it induces the accumulation of ubiquitinylated proteins suggesting inhibition of the ubiquitin-proteasome pathway, leading to the apoptotic death of cancer cells.

The subject of the present invention is thus a compound of the following general formula (I): ## STR1 ## as well as its pharmaceutically acceptable salts, isomers and isomeric mixtures in all proportions, in particular a mixture of enantiomers, and especially a racemic mixture, for which: is absent or represents a single bond, represents a single bond or a double bond, when Ai- - () represents A0, then A1O represents A. O, and Al represents a group CH, C- OR4, C-SR5 or CNR15R16, preferably C-OR4 or C-SR5, and A2 is a carbon atom, when Ai--O is absent, then A1O is AI O, and Al is a carbon atom and A2 is a CH, C-OR6 or C-SR17 group, and preferably a C-OR6 or C-SR17 group, and more preferably a C-OR6 group, A3 represents a C = CH2 group or a CH-CH2R7 group, R represents a group CH3, CH2F, CF3, CH2, CH2, CH2OH, CH2OR8, CH2OCOR8 or C H2OC (O) NR8, and preferably a CH3, CH2OR8 or CH2OCOR8 group, and more preferably CH3, when the bond between the carbons 1 and 2 is a double bond, while R1 represents a hydrogen atom, when the bond between the carbons 1 and 2 is a single bond, then R 1 represents a hydrogen atom or a group OR 9, SR 10 or NR 11 R 12, or R 1 forms with R 6 a bond connecting the carbon atoms and oxygen which carry them so as to form an epoxide between carbons 1 and 10, - R2 represents a hydrogen atom or a group OR13, where R2 forms with R6 a bond connecting the carbon and oxygen atoms which carry them. to form an epoxide between carbons 14 and 10, and - R3 represents a group -X-R14, X represents a CO or C (O) N group or a bond,

with: - R 4 representing a hydrogen atom or a (C 1 -C 6) alkyl group optionally substituted by one or more halogen atoms, - R 5 representing a (C 1 -C 6) alkyl group optionally substituted with an OH group or (C 1 -C 6) alkoxy, - R 6 representing a hydrogen atom or a (C 1 -C 6) alkyl group, -CO- (C 1 -C 6) alkyl, aryl- (C 1 -C 6) alkyl, benzyloxy- ( C, -C 6) alkyl or SiRaRbR °, the (C 1 -C 6) alkyl unit of said group being optionally substituted with one or more halogen atoms and the aryl or benzyl unit of said group being optionally substituted by a group (C 1 -C 6); C6) alkoxy, or R6 forming with R1 a bond connecting the carbon and oxygen atoms that carry them to form an epoxide between carbons 1 and 10, or R ° forming with R2 a bond connecting the carbon atoms and of oxygen carrying them so as to form an epoxide between carbons 14 and 10, or R6 and R14 together forming a chain - (CH2) n -O- (CH2) m- with n and m representing, independently of one another, an integer between 1 and 3, and preferably each representing 1, R7 representing an atom of hydrogen or a group OR18, SR19 or NR20R21, and preferably represents a group OR18, SR19 or NR2 ° R21, representing a (C1-C6) alkyl group optionally substituted with one or more halogen atoms, R9 and R18 representing, independently from each other, a hydrogen atom or a (C 1 -C 6) alkyl group optionally substituted by one or more groups selected from a halogen atom and an OH, (C 1 -C 6) alkoxy group, aryl and -O-CO- (C 1 -C 6) alkyl, R 10, R 17 and R 19 representing, independently of each other, a (C 1 -C 6) alkyl group optionally substituted with an OH group, (C 1 -C 6) alkoxy or -O-CO- (C 1 -C 6) alkyl, R 11 and R 12 represent, independently of one another, a hydrogen atom or an OH, (C 1 -C 6) alkyl or ryl- (C 1 -C 6) alkyl, R 11 and R 12 can not simultaneously represent an OH group, or R 11 and R 12 forming with the nitrogen atom which carries them a 5- or 6-membered heterocycle, optionally comprising, more than the nitrogen atom, one or more heteroatoms selected from oxygen, sulfur and nitrogen, and being optionally substituted by a (C 1 -C 6) alkyl group, R 13 representing a hydrogen atom or a group 0 -protecteur, such as a group (C, -C6) alkyl, -CO - ((C, -C6) alkyl), SiRaRbR °, or -SO2CF3r R14 representing a group (C, -C6) alkyl, (C, C6) epoxyalkyl, (C2-C6) alkenyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C5-C, O) polycycloalkyl, aryl- (C1-C6) alkyl, benzyloxy (C 1 -C 6) alkyl, aryl or heteroaryl, the aryl, benzyl or heteroaryl unit of said group being optionally substituted by one or more groups selected from a halogen atom and a (C 1 -C 6) alkoxy, aryl or NR22R23, R1 And R 16 represents, independently of one another, a hydrogen atom or an OH, (C 1 -C 6) alkyl or aryl (C 1 -C 6) alkyl group, R 15 and R 16 can not simultaneously represent a OH group, or R15 and R'6 forming with the nitrogen atom which carries them a 5- or 6-membered heterocycle, optionally comprising, in addition to the nitrogen atom, one or more heteroatoms chosen from oxygen, a sulfur and a nitrogen, and being optionally substituted by a group (C1-C6) alkyl, R20 and R2 'representing, independently of one another, a hydrogen atom or an OH group, (Cl-C6) alkyl or aryl- (C1-C6) alkyl, R20 and R2 'can not simultaneously represent an OH group, or R20 and Rn forming with the nitrogen atom which carries a 5- or 6-membered heterocycle, optionally comprising , in addition to the nitrogen atom, one or more heteroatoms selected from oxygen, sulfur and nitrogen, and being optionally substituted by a groupem ent (C1-C6) alkyl, R22 and R23 representing, independently of one another, a hydrogen atom or a group (C1-C6) alkyl, and Ra, Rb and R ° represent, independently of one of the other, a (Cl-C6) alkyl group,

with the exception of: tagitinin C and tagitinin F, compounds for which Ai-O represents C-O, AlO represents A0, the bonding between carbons 1 and 2 represents a single bond, Al represents a group C-OH or C-OCH3r A3 represents CH = CH2, R represents a group CH3, R1 represents a group OCH3 or OH, R2 represents a hydrogen atom and R3 represents a group -C (O) CH (CH3 ) 2 or -C (O) C (CH3) = CHCH3r and compounds for which A2 - O is absent and A2 represents C - OH, AlO represents C = O, the bond between carbons 1 and 2 represents a double bond , A3 represents CH = CH2, R1 and R2 each represent a hydrogen atom and either R represents a CH3 group and R3 represents a -C (O) CH (CH3) 2 or -C (O) C (CH3) group. = CHCH3r where R is CH2OH and R3 is O

For the purposes of the present invention, halogen is understood to mean a fluorine, bromine, chlorine or iodine atom. Advantageously, it is fluorine, bromine or chlorine and still advantageously fluorine or chlorine. For the purposes of the present invention, the term "(C 1 -C 6) alkyl" is intended to mean a linear or branched saturated hydrocarbon-based chain containing 1 to 6, preferably 1 to 4, carbon atoms. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups. Advantageously, it is methyl, ethyl, propyl, isopropyl or butyl. When the (C1-C6) alkyl group is substituted by one or more halogen atoms, preferably fluorine or chlorine, it may be the following groups: -CF3, -CH2F, -CH2CC13, -CH2CF3, - CH2CH2F. Advantageously, these groups will be -CH2CC13, -CH2CF3 and -CH2CH2F. For the purposes of the present invention, the term "(C 1 -C 6) epoxyalkyl" means a (C 1 -C 6) alkyl group, as defined above, substituted by an epoxide function, that is to say two Adjacent carbon atoms are bonded by an oxygen atom. For the purposes of the present invention, the term "(C2-C6) alkenyl" means a linear or branched hydrocarbon-based chain containing at least one double bond and containing 2 to 6 carbon atoms. By way of example, mention may be made of pentenyl, isopropenyl, butenyl (such as buten-3-yl), 1-methylpropen-1-yl (-C (CH 3) = CHCH 3) or else 2-methylpropen-1 yl (-CH = C (CH3) 2). Advantageously, it is buten-3-yl, 1-methylpropen-1-yl or 2-methylpropen-1-yl. For the purposes of the present invention, the term "(C 3 -C 7) cycloalkyl" means a saturated cyclic hydrocarbon chain containing 3 to 7 carbon atoms. By way of example, mention may be made of cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl groups. Advantageously, it is cyclopropyl, cyclopentyl or cyclohexyl. For the purposes of the present invention, the term "polycycloalkyl" (C 5 -C 10) is intended to mean a saturated hydrocarbon chain containing 5 to 10 carbon atoms and comprising at least 2, advantageously 2 or 3, contiguous rings. By way of example, mention may be made of the adamantyl group. For the purposes of the present invention, the term "(C1-C6) alkoxy" means a (C1-C6) alkyl group, as defined above, linked to the molecule via an oxygen atom. By way of example, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy or even tertbutoxy groups. Advantageously, these are methoxy groups. For the purposes of the present invention, the term "aryl" means an aromatic group, preferably comprising from 5 to 10 carbon atoms, and comprising one or more contiguous rings, for example a phenyl or naphthyl group. Advantageously, it is phenyl. By heteroaryl or heteroaromatic means, within the meaning of the present invention, any aryl group as defined above in which one or more carbon atoms have been replaced by one or more heteroatoms advantageously 1 to 4 and, even more advantageously 1 to 2, such as, for example, sulfur, nitrogen or oxygen atoms.

Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl or indyl groups. For the purposes of the present invention, the term "5- or 6-membered heterocycle" means a 5- or 6-membered ring, saturated or non-saturated, but not aromatic, and containing one or more, advantageously 1 to 4, even more advantageously 1 or 2, heteroatoms, such as, for example, sulfur, nitrogen or oxygen atoms. Advantageously, the heterocycle will be saturated. Moreover, it comprises at least one nitrogen atom since it corresponds, in the present invention, to the NR11R12 or NR20R21 group. It may especially be pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group. Advantageously, these are piperidinyl, morpholinyl or piperazinyl groups, the free nitrogen of the piperazinyl group being optionally substituted with a (C 1 -C 6) alkyl group as defined above, and in particular with a methyl. By (C3-C7) cycloalkyl- (C1-C6) alkyl is meant, within the meaning of the present invention, a (C3-C7) cycloalkyl group, as defined above, linked to the molecule via a (C1-C6) alkyl chain as defined above. By way of example, mention may be made of cyclopropyl-methyl, cyclohexyl-methyl and cyclopentyl-ethyl groups, and advantageously cyclohexyl-methyl groups.

By benzyloxy- (C1-C6) alkyl is meant, in the sense of the present invention, a benzyloxy group (C6H5-CH2O-) linked to the molecule via a (C1-C6) alkyl chain, such as defined above. By way of example, mention may be made of benzyloxymethyl group.

For the purposes of the present invention, aryl- (C1-C6) alkyl is understood to mean an aryl group, as defined above, linked to the molecule via a (C1-C6) alkyl chain, as defined above. By way of example, mention may be made of the benzyl group. For the purposes of the present invention, the term "protecting group" is intended to mean any substituent which protects the hydroxyl or carboxyl group, ie a reactive oxygen atom, against the undesirable reactions such as the O-protecting groups described. in Greene, "Protective Groups In Organic Synthesis", (John Wiley & Sons, New York (1981)) and Harrison et al. Compendium of Synthetic Organic Methods, 1 to 8 (J. Wiley & Sons, 1971 to 1996) O-protecting groups include methyl or substituted or unsubstituted alkyl ethers, for example, methoxymethyl, benzyloxymethyl, 2 methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl, benzyl and triphenylmethyl, benzyl ethers (substituted or unsubstituted), tetrahydropyranyl ethers, allyl ethers, substituted ethyl ethers, for example, 2.2, 2-trichloroethyl, silyl ethers or alkylsilyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, heterocycle ethers and esters prepared by reaction of the hydroxyl group with a carboxylic acid for example, tert-butyl, benzyl or methyl esters, carbonates, in particular benzyl or haloalkyl carbonate, acetate, propionate, benzoate, triflate and the like. Advantageously, it is an ester of the -CO-alkyl type, such as an acetate, or an alkylsilyl, such as trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS) or triisopropylsilyl (TIPS) groups. Preferably, it is an acetate or a TBDMS. In the present invention, the term pharmaceutically acceptable is understood as being useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary as well as human pharmaceutical use. By pharmaceutically acceptable salts of a compound are meant in the present invention salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound. Such salts include: (1) hydrates and solvates, (2) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, acid nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, acid methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like; and (3) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion (Na +, K + or Li + for example), an alkaline earth metal ion ( as Cal + or Mg2 +) or an aluminum ion; either coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. In the present invention, is meant by isomers diastereoisomers or enantiomers. It is therefore optical isomers also called stereoisomers. Stereoisomers that are not mirror images of each other are thus referred to as diastereoisomers, and stereoisomers that are mirror images but not superimposable are referred to as enantiomers. A carbon atom bonded to four nonidentical substituents is called a chiral center. An equimolar mixture of two enantiomers is called a racemic mixture.

For the purposes of the present invention, it is understood that there is no bond between A2 and 0. When the bond between carbons 1 and 2 is a double bond, it may be of Z configuration or E. It will be of Z configuration (that is, the R1 group and the carbon-2-substituted hydrogen atom are located on the same side of the link) when Al 1 O represents Al O, and it will be configuration E or Z, and preferably E (i.e., the group R 1 and the hydrogen atom are located on either side of the bond) when Al 2 O represents AI = O

According to a first aspect, a compound according to the invention can satisfy the following formula (Ia): OR3

(Ia) with Z1 representing a hydrogen atom or a group OR6 or SRI ', preferably a group OR6 or SRI', and more preferably a group OR6, and R, R1, R2, R3, R6, R'7 , A3 and being as defined above. In this case, R6 will preferably represent a hydrogen atom or a (C1-C6) alkyl, -CO- (C1-C6) alkyl, aryl- (C1-C6) alkyl or benzyloxy- (C1-C6) group. ), the (C1-C6) alkyl unit of said group being optionally substituted by one or more halogen atoms and the aryl or benzyl unit of said group being optionally substituted by a (C1-C6) alkoxy group. In particular, R 6 may represent a hydrogen atom or a methyl, acetyl or benzyloxymethyl group, or according to a second aspect, a compound according to the invention may have the following formula (Ib): R 1 R 2 O R 3 Z 2 " (Ib) with Z2 representing a hydrogen atom or a group OR4, SR5 or NR15R16, and preferably a group OR4 or SR5, and R, R1, R2, R3, R4, R5, R15, R16, A3 and - being as defined above. Preferably, the compounds of the invention will be in the open form (1a). Advantageously, the group OR 3 will be on the same side of the 10-membered ring as the group A3, that is to say that the compounds of the invention will correspond to the following formula (Ic): ## STR3 ## R2, R3, Al, A2, A3, and being as defined above. Advantageously, R represents a group CH3, CHO, CH2OH, CH2OR8 or CH2OCOR8. Preferably, it is a CH3, CHO, CH2OH, CH2OCH3 or CH2OCOCH3 group. Still more preferably, R is CH3, CH2OCOCH3 or CH2OCH3. More preferably, R represents a CH3 group. Advantageously, R2 represents a hydrogen atom or an OH, OCOCH3 or OSi (CH3) 2tBu group. Preferably, it is a hydrogen atom. Preferably, R 1 is on the same side of the 10-membered ring as A3, i.e. the compounds of the invention will have the following formula (Id): R3 (Id), R, R1 , R2, R3, Al, A2, A3, and - being as defined above. Advantageously, when the bond between carbons 1 and 2 is a single bond, R 1 does not form a bond with R 6 and represents a group OR 9, SR 10 or NR 11 R 12.

According to a first particular embodiment of the invention, R1 does not represent a hydrogen atom and / or A3 does not represent a CH = CH2 group. In this case, R1 will represent a group OR9, SR10 or NR11R12 and / or A3 will represent a group CH-CH2R7, with R7 representing a group OR18, SR19 or NR20R21. In this case, R3 preferably represents a -CO (C1-C6) alkyl group, the (C1-C6) alkyl group being preferably an isopropyl group. Similarly, R advantageously represents a CH 3 group and R 2 advantageously represents a hydrogen atom. Thus, advantageously, R 1 will represent a group OR 9, SR 10 or NR 11 R 12 and / or A3 will represent a group CHCH 2 R 7, with R 7 representing a group OR 18, SR 19 or NR 20 R 21, R will represent a group CH 3, R 2 will represent a hydrogen atom, R 3 will represent a -CO (C 1 -C 6) alkyl group, and preferably a -CO-CH (CH 3) 2 group, with Al, A2, R 9, R, R '' R 12 R 18 R 19 R 20 R 21, and as defined above. Advantageously, R1 represents NR11R12 and / or R7 represents NR20R21. Preferably, R1, R3 and A3 will be located on the same side of the 10-membered ring (when in a chemical sense).

According to a second particular embodiment of the invention, R3 represents: ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## (ie, in this case, X represents a bond), COR24 (in this case, X = CO), with R24 representing (C3-C7) cycloalkyl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C5-Clo) polycycloalkyl, aryl- (C1-C6) ) alkyl, benzyloxy- (C1-C6) alkyl, aryl or heteroaryl, the aryl, benzyl or heteroaryl unit of said group being optionally substituted by one or more groups selected from a halogen atom and a (C1-C6) alkoxy group, aryl or NR22R23, with R22 and R23 as defined above. In this case, A3 will advantageously represent a C = CH2 or CH-CH2NR2oR21 group, in particular with NR2oR2 'representing a morpholinyl group. Preferably, A3 will represent a group C = CH2. R will advantageously represent a CH3, CH2OC (O) CH3 or CH2OCH3 group and preferably will represent a CH3 group. Moreover, R2 will advantageously represent a hydrogen atom, R1 will advantageously represent a hydrogen atom and the bond between carbons 1 and 2 will advantageously be a double bond. Advantageously, A1O will represent a C = O bond and therefore A2 will represent a C-OR6 or C-SR '' group, and preferably a C-OR6 group, with R6 and RF 'as defined above.

In particular, the compound of the invention may be selected from.

EtO PrO BuO HO iPrO EtS HO "" 'CF3CCH2O "" F3CCH2O "HO O r OCOiPr O HOCN ~ CHZC6H5 HO" "OCOiPr HOC ~ CHZC6H5 N HO" OM O OMe O OMe OMe o and The present invention also for A compound of the invention as defined above for its use as a medicament, in particular for the treatment of cancer, The present invention also relates to the use of a compound according to the invention for the preparation of a The present invention also relates to a method of treating cancer, comprising administering a sufficient amount of a compound of the invention to a patient in need thereof.

The present invention also relates to a pharmaceutical composition comprising at least one compound of the invention as described above in association with a pharmaceutically acceptable vehicle. The compounds according to the invention can be administered orally, sublingually, parenterally, subcutaneously, intramuscularly, intravenously, transdermally, locally or rectally, and preferably by oral or intravenous means. In the pharmaceutical compositions of the present invention for oral, sublingual, parenteral, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredient may be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, animals or humans. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, parenteral forms of administration, -cutaneous, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration. When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.

A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules. A syrup or elixir preparation may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable colorant. Water-dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, as well as with taste correctors or sweeteners. For rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols. For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersing agents and / or pharmacologically compatible wetting agents are used. The active ingredient may also be formulated as microcapsules, optionally with one or more additive carriers.

The compounds of the invention can be used at doses of between 0.01 mg and 1000 mg per day, given in a single dose once a day or administered in several doses throughout the day, for example twice per day. day in equal doses. The dose administered per day is advantageously between 5 mg and 500 mg, more advantageously between 10 mg and 200 mg. It may be necessary to use doses out of these ranges which the skilled person can realize himself. According to a particular embodiment, the pharmaceutical composition of the invention, as defined above, may further comprise at least one other active ingredient, in addition to the compound of the invention, and preferably an anticancer agent. As examples of active ingredients that can be combined with the compound of the invention in a pharmaceutical composition, mention is made, without limitation, of 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, ana strazole, letrozole, tamoxifen, octreotide and lanreotide. The present invention also relates to a pharmaceutical composition comprising: (i) at least one compound of formula (I) as defined above, and (ii) at least one other active ingredient, in particular useful for the treatment of cancer, as combination products for simultaneous, separate or time-spread use. As active principle, there may be mentioned, in particular, but not limited to, 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide , nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrazole, letrozole, tamoxifen, octreotide or lanreotide. The present invention also relates to the use of a pharmaceutical composition comprising: (iii) at least one compound of formula (I) as defined above, and (iv) at least one other active ingredient, in particular useful for cancer treatment as combination products for simultaneous, separate or time-course use in the manufacture of a medicament for the treatment of cancer. The present invention also relates to a pharmaceutical composition as defined above for its use as a medicament in the treatment of cancer.

The subject of the present invention is also a process for the synthesis of a compound of formula (I) in which R 1 represents a group OR 9, SR 10 or NR "R 14 and / or A3 represents a group CH-CH 2 R 7, with R 7 representing a grouping OR18, SR19 or NRzoRz1 and R9, wherein R1 and R21 are as defined above, characterized in that the compound of formula (I) is prepared by a Michael reaction between a compound of formula (II) below R 2 for which Al, A2, R, R 2, R 3, and - are as defined above, and a nucleophile of formula R 1 H and / or R 7 H, with R 1 and R 7 as defined above.

It should be noted that the double bond between carbons 1 and 2 is Z configuration if there is an oxygen bridge between Al and A2, and configuration E or Z, preferably E, if the oxygen bridge does not exist. Preferably, the Michael reaction will be carried out from a compound of the following structure (IIa): OR3 (IIa), for which R, R2, R3 and Z1 are as defined above. This reaction may be carried out in the presence of titanium tetraisopropylate as a reaction catalyst.

Even more preferably, the compound of formula (II) will be tagitinin C thus making it possible to give access to compounds of formula (I) for which R1 represents a group OR9, SR10 or NR11R12 and / or A3 represents a CH-CH2R7 group, with R7 representing a group OR18, SR19 or NR20R21, and R = CH3, R2 = H, R3 = CO-CH (CH3) 2 and: A2 = C-OH and Al = C when A1O represents C = O or A2 = C and Al = C-OH when AlO is A0. Additional functionalization steps, well known to those skilled in the art, may then make it possible to give access to the other compounds of formula (I) for which R 1 represents a group OR 9, SR 10 or NR 11 R 12 and / or A3 represents a group CH-CH 2 R 7 . Moreover, the compound thus obtained can be purified by conventional purification methods known to those skilled in the art such as by crystallization or column chromatography. Two bonds are capable of undergoing Michael addition, namely C = C double bonds at the 1,2 or 11,13 position, the 1,2-bond bond being reactive however only when the molecule (II) is in its open form, that is to say in the form (IIa). Depending on the nucleophile used in this Michael reaction, it will thus be possible preferentially to obtain the addition on the double bond of the enone in the 1,2 position or on the exomethylene of the lactone at the 11,13 position, or it will be possible to obtain a mixture of different adducts resulting either from the monoaddition of the nucleophile on the C = C bond at the 1,2 or 11,13 position, or the diaddition of the nucleophile on the C = C bonds in position 1,2 and 11, 13. However, for the addition on the C = C double bond in the 1,2 position to take place, the starting molecule must be in the open form (IIa), that is, the double bond must be effectively conjugated with a carbonyl.

Thus, if R 1 and R 7 do not each represent a hydrogen atom, it is conceivable to carry out the reaction with a single nucleophile R 1 H = R 7 H when R 1 = R 7, or to carry out two successive Michael reactions with two different nucleophiles. R1H and R7H. When the nucleophile is an alcohol or a thiol, that is to say that it carries an OH or SH function, then the nucleophile will add preferably on the carbon atom 1. In this case, the R1 group thus introduced will preferably be located on the same side of the 10-membered ring as A3. When the nucleophile is an amine, i.e., it carries an NH or NH 2 function, then the Michael reaction will generally lead to a mixture of compounds. In this case, the open form (i.e. there is no oxygen bridge between Al and A2) will be stabilized and predominant (preferably as 1113-13-amino-tagitinin C compounds). and 1I3, 1113-1, 13-diamino-tagitinin C).

The subject of the present invention is also a process for the synthesis of a compound of the following formula (Ie): (Ie) as well as its pharmaceutically acceptable salts, its isomers and isomeric mixtures in all proportions, in particular a mixture of enantiomers, and especially a racemic mixture, for which: is absent or represents a single bond, represents a single bond or a double bond, when A 1 () is A2 O, then A4O represents A4O and A4 represents a C moiety -OH, and A2 represents a carbon atom, - when A2-- O is absent, then A4.uO represents A4u0, and A4 represents a carbon atom and A2 represents a group C-OR6, and - R6 and R3 are such that defined above, from tagitinin C of the following formula: characterized in that the process comprises the following successive steps. (1) optionally protecting the enone function in position 1-3 and / or protecting the double bond C = CH 2 in position 11-13, (2) hydrolyzing the isopropyl ester in position 8 to give the corresponding alcohol (3) converting the alcohol obtained in the preceding step (2) into an OR 3 group, and optionally converting the alcohol at the 10-position to the OR 6 group when R 6 does not represent a hydrogen atom, (4) optionally deprotecting the enone function at the 1-3 position and / or deprotecting the double bond in position 11-13, and (5) isolating the compound (Ie) thus obtained.

The compounds of formula (Ie) are therefore part of the compounds of formula (I).

The compounds thus obtained may undergo one or more additional functionalization steps in order to access the other compounds of formula (I), in particular those for which R 3 does not represent a COCH (CH 3) 3 group. Advantageously, R 3 will represent an R 14 grouping. or COR14 with R14 as previously defined.

Step 1 The protection of the enone function can be carried out either by protecting the C = C double bond or by deactivating the carbonyl. Advantageously, this protection will be effected by deactivating the carbonyl by reducing this function to alcohol followed by the protection of the alcohol with an O-protecting group as defined above. The reduction of the carbonyl function will advantageously be carried out by reaction with a sodium borohydride such as NaBH (OCH3) 3 in the presence of CeC13. The alcohol thus obtained will preferably be protected in the form of a silyl ether, and in particular by a TBDMS group, by reaction in particular with RaRbR °SiCl, Ra, Rb and R ° being as defined above, and preferably with TBDMSC1. . Protection of the C = CH 2 double bond will preferably be carried out by addition on carbon 13 of a protective group of activated double bonds as defined below. It may be in particular an amine of formula HNR'R "with R 'and R" as defined below, and more particularly of a heterocycle or a heteroaromatic having an intracyclic NH group such that imidazole or morpholine. It may be envisaged to protect the alcohol function and the double bond simultaneously (especially in the presence of TBDMSC1 and imidazole) or successively (in particular by protecting the alcohol with a TBDMS group and protecting the C = C double bond with morpholine).

Step 2 The hydrolysis of the isopropyl ester can be carried out enzymatically or chemically. Enzymatic hydrolysis can be carried out in particular on tagitinin C or on 3-hydroxy-tagitinin C. It can be carried out using an esterase and in particular by using crude porcine esterase of liver or horse esterase of liver. The chemical hydrolysis can be carried out in the presence of an alkali metal (C1-C6) alkoxylate, the alkali metal being in particular sodium or potassium.

This will be in particular sodium methoxylate. The solvent may be in particular an alcohol such as methanol or ethanol, and preferably methanol. The reaction can be carried out at room temperature.

Step 3 The conversion of the alcohol to C-8 to a group OR3 may be carried out in the presence of an acyl chloride of formula R3COC1 to form an ester, of a halogenated derivative of formula R3Ha1 (with Hal representing an atom of halogen and in particular a chlorine or bromine atom) to give an ether or an isocyanate of formula R3-N = C = O to give a carbamate. The conversion of the alcohol to C-10 to an OR6 group (with R6 H) may be carried out in the presence of a halogenated derivative of formula R6Ha1 (with Hal representing a halogen atom and in particular a chlorine or bromine atom ). The conversion of the two alcohols can in particular be carried out simultaneously, especially in the presence of R6Ha1 = R3Ha1.

Additional steps of protection / deprotection of the alcohol at C-10 may be envisaged when the conversion of this alcohol to a group OR6, with R6 H, is not desired, and in particular when the conversion is carried out in the presence of a halogenated derivative, thereby giving access to ether derivatives (i.e., when X is a bond).

Step 4 This step will only be performed if step 1 has been completed. When the carbonyl of the enone function in position 1-3 is converted into silylated ether, the alcohol may be deprotected in the presence of fluoride ions, especially in the presence of tetrabutylammonium fluoride (TBAF), and then oxidized, especially in the presence of MnO 2r BaMnO4, tetrapropylammonium perruthenate (TPAP) or Dess-Martin reagent, to regenerate the carbonyl function. When the C = CH2 function is protected with imidazole, it can be deprotected with TBAF. In the case of protection with morpholine, the double bond may be regenerated by the action of methyl iodide (Ananthasubramanian L. et al., Indian Journal of Chemistry 1978, 16B, 191-195).

Deprotections of the alcohol and the C = CH 2 function may also be simultaneous (in particular in the case of protection of the alcohol with TBDMSC1 and function C = CH2 with imidazole, the deprotection can be carried out in this case with TBAF), either successive.

Step 5 The isolation of the compound (Ie) obtained can be carried out by techniques well known to those skilled in the art such as by simple evaporation of the solvent, extraction, distillation, crystallization, etc.

The compound thus obtained may be purified if necessary by methods well known to those skilled in the art such as by distillation, silica gel chromatography, HPLC (High Performance Liquid Chromatography), recrystallization, etc.

Furthermore, the introduction of a functional group at the C-15 position can be carried out from the 15-hydroxytagitinyl angelate isolated from Helianthus annuus (Spring, O. et al., Photochemistry 1982, 21, 2551-2553) by techniques well known to those skilled in the art (in particular by oxidation, nucleophilic substitution, etc.).

The introduction of a substituent R2 H can be carried out from heliangolide precursors such as rotundin, extracted from Tithonia rotundifolia (Bohlmann, F. et al., Photochemistry 1981, 20, 267-270). The desired R2 substituent is first introduced from the heliangolide precursor by techniques well known to those skilled in the art and then the derivative is oxidized in the presence of chromic anhydride / acetic acid or Dess-Martin reagent to open the epoxide present between carbons 1 and 10 and to form the double bond between carbons 1 and 2.

In addition, the C-8 carbon configuration 13 could be reversed by a Mitsunobu reaction, well known to those skilled in the art, from a derivative having a C-8 alcohol function (especially a compound of formula (IIIa) or (IIIb) described below and whose synthesis is described above). It would then be sufficient to functionalize with a group R3 the alcohol in C-8 configuration thus obtained.

The compounds of the invention may thus be prepared by a combination of the various reactions described above, in particular from tagitinin C, in order to introduce the various substituents, additional steps of protection / deprotection and / or functionalization, well known to those skilled in the art, may be necessary.

The subject of the present invention is also a compound of the following formula (IIIa) or (IIIb): OH OH OH (IIIa) or (IIIb), as well as its pharmaceutically acceptable salts, isomers and mixtures of isomers in all proportions , in particular a mixture of enantiomers, and in particular a racemic mixture,

for which: represents a single bond or a double bond, - R1 represents a hydrogen atom when it represents a double bond or represents a hydrogen atom or a group OR9, SR10 or NR "R12, with R9, R'0 , R11 and R'2 as defined above, when - - represents a single bond, A5 represents a group C = O, CH-OH or CH-OGP1, where GP1 represents an O-protecting group such as a SiRaRbR ° group, where Ra, Rb and R ° represent, independently of one another, a (C1-C6) alkyl group, A6 represents a C = CH2 or CH-CH2GP2 group, where GP2 represents a double bond protecting group; such as an imidazolyl or morpholinyl radical, and A7 represents a hydrogen atom or an OH or OGP3 group, where GP3 represents an O-protecting group such as a (C, -C6) alkyl or SiRdReRf group, with Rd , Re and Rf representing, independently of each other, a (C 1 -C 6) alkyl group.

These compounds are particularly useful as synthesis intermediates in the process of introducing an R 3 substituent (other than the COCH (CH 3) 2 group) in the 8-position described above (compound obtained in step 2 of the process). The compounds of formula (IIIa) are particularly useful as synthesis intermediates.

For the purposes of the present invention, the term "protecting group of activated double bonds" means any substituent which protects an activated C = C function such as an exomethylene of a lactone against undesirable reactions. It may be in particular a (C 1 -C 6) alkoxy, -S- (C 1 -C 6) alkyl group, or alternatively -NR 'RR "where R' and R" represent, independently of one of the other, a hydrogen atom, a (C 1 -C 6) alkyl or aryl (C 1 -C 6) alkyl group or R 'and R "form, with the nitrogen atom which carries them, a 5-membered heterocyclic ring; or 6-membered, optionally having, in addition to the nitrogen atom, one or more heteroatoms selected from oxygen, sulfur and nitrogen, Advantageously, it will be an imidazolyl or morpholinyl radical.

Advantageously, the hydroxyl group in position 8 will be located on the same side of the 10-membered ring as the radical A6. Preferably, R 1 represents either a hydrogen atom when it represents a double bond, or a group OR 9, SR 10 or NR 11 R 12, and preferably OR 9, when represents a single bond (with R 9, R 10, R "and R '2 such that defined above, R 9 advantageously representing a hydrogen atom or a (C 1 -C 6) alkyl group, Preferably A 7 represents an OH or (C 1 -C 6) alkoxy group.

The compounds of formula (IIIa) and (IIIb) can be in particular the following compounds: ## STR1 ## The present invention also relates to a process for the preparation of a compound of formula (IIIa) or (IIIb) for which R1 represents a hydrogen atom and represents a double bond from tagitinin C of the following formula: characterized in that the process comprises the following successive steps. (a) optionally protecting the enone function at position 1-3 and / or protecting the C = CH 2 double bond at position 11-13, (b) hydrolyzing the isopropyl ester at position 8 to give the corresponding alcohol (c) optionally deprotecting the enone function at the 1-3 position and / or deprotecting the double bond in the 11-13 position, and (d) isolating the compound (IIIa) or (IIIb) thus obtained.

The same remarks as those indicated above for steps (1), (2), (4) and (5) of the process for preparing a compound (Ie) also apply to steps (a), (b ), (c) and (d). The invention will be better understood on reading the examples which follow, these examples serving only to illustrate the invention and not to limit its scope.

EXAMPLES

EXAMPLE 1 Synthesis of the compounds of the invention

Preferably, the manipulations will be carried out in the absence of light when they involve a compound containing a photosensitive dienone unit.

1.1. Preparation of 113-methoxy-tagitinin F 1.1.1. By extraction of Tithonia diversifolia with methanol 100g of ground leaves of Tithonia diversifolia are macerated in the dark in 600 ml of methanol for 24 hours. After filtration of the extract I on celite, the filtrate I is evaporated and the grounds are taken up in 600 ml of methanol. After 10 days of maceration, the extract II is filtered and evaporated. The evaporation residues of the two extracts are dissolved in 100 ml of ethyl acetate supplemented with activated charcoal. After filtration on celite and concentration of the filtrates, the dry residues are purified by medium pressure chromatography (MPC). The column is eluted by the following linear gradient. t = 0 min cyclohexane: AcOEt 70: 30 t = 30 min cyclohexane: AcOEt 70: 30 t = 1h00 cyclohexane: AcOEt 50: 50 t = 2h00 cyclohexane: AcOEt 50:50 After analysis of the fractions eluted by thin layer chromatography ( TLC) (eluent: cyclohexane: AcOEt 50:50), the identical fractions and the concentration are combined. In the order of elution, 1S-methoxy-tagitinin F / C 35 (9/1 in solution in the solvent) is obtained. NMR) (235.5 mg), tagitinin F (35.01 mg), tagitinin C (374.1 mg) and tagitinin A (459.6 mg).

NB: F / C means that the open form (C form) and the closed form 5 form F form equilibrium in solution

113-Methoxy-tagitinin F / C MeO HO "'(equilibrium with minority open form not shown) Open form (F): 1H-NMR: .0.99 (d, J 7, 0, 3H), 1.01 (d, J 7, 0.3H), 1.48 (s, 3H), 1.65 (dd, J 14.7 / 4.8, 1H), 1.77 (t, J 1, 8, 3H), 2.03 (dd, J 12.3 / 10.7, 1H), 2.15 (m, 1H), 2.38 (sep, J, 7.0, 1H), 2, 48 (dd, J 12.6 / 6.4, 1H), 3.34 (s, 3H), 4.00 (dd, J 10.7 / 6.4, 1H), 4.08 (m, 1H). ), 5.47 (m, 1H), 5.55 (dq, J 2.7 / 1.5, 1H), 5.66 (d, J 2, 2, 1H), 6.11 (d, J); 2, 7, 1H) 13C-NMR: 18, 9, 19.0 (2C), 22, 4, 27, 0, 35, 3, 35, 9, 43, 2, 50, 4, 59, 0, 72, 1, 76, 5, 87, 2, 103, 9, 122, 9, 128, 8, 142, 6, 170, 8, 176.3 Mass: 403 (M + 23 = 380 + Na)

1.1.2. By the action of titanium tetraisopropylate on tagitinin C, a solution of tagitinin C (20 mg, 0.057 mmol) in methanol (500 μL) was added titanium tetraisopropoxide (0.5 μL, 0.014 mmol, 0.25 eq. ). The mixture is then heated to 70 ° C. After 4 h, titanium tetraisopropoxide (2 μl, 1 eq) is added. After 1 h, 50% of tagitinin C reacted; the reaction is terminated by diluting the reaction mixture with cyclohexane (500 μl). The solution is filtered on an SPE column (Sep-Pak Interchim cartridges) of silica gel (eluent: cyclohexane / ethyl acetate 7: 3). The collected fractions are evaporated and the residue is purified on an SPE column of silica gel (eluent: cyclohexane / ethyl acetate 7: 3). 15 mg of 1-methoxy-Tagitinin F / C (Yield 75%), 0.50 mg of methyl-secoester of 1-methoxy-tagitinin C (Yield 2%), and 2 mg of tagitinin C which do not has not reacted.

1.2. Other Additions of Alcohols and Thiols to Tagitinin C General Procedure A solution of tagitinin C in an alcohol or thiol solvent is kept at room temperature in the light for one week. The reaction is monitored by TLC. The solvent is then evaporated and the residue is purified on an SPE column of silica gel. The following derivatives were thus prepared: 1-ethoxy-tagitinin F 1 H-NMR: ............................ ................................ .................. .......................................... 4,09 2,04 (dd ) 12.4 / 6.5 2.45 5.55 (m) 5.47 (m) 4.09 5.59 (dt) 11.4 / 4.7 1.66 (dd) 14.8 / 4 , 2.15 (masked) 5.66 (d) 2.5 6.11 (d) 2.7 1.48 40, 76 (t) 1.9 2.38 (7) 7.0 0.99 (d) 7.1 1.01 (d) 7.0 3.53 (q) 6.9 1.13 (t) 7.0 3.82 (d) 1.3 1-propoxy-tagitinin F Pro HO "" '1H-NMR ............................................ .............................. .................... .................................................. .... .................................................. ......................... 4.07 (dd) 10.7 / 6.6 2.04 (t) 12.3 2.45 (dd) 12.6 / 6.6 5.55 (m) 5.47 (m) 4.09 5.59 (dt) 11.5 / 4.7 1.66 (dd) 14.7 / 4.9 2.17 (dd) 14.2 / 11.7 5.66 (d) 2.2 6, 11 (d) 2.7 1.48 1.76 (t) 1.8 2.38 (7) 6.9 0.99 (d) 7.3 1.01 (d) 6.9 3.82 (b) d) 1.3 3.44 (t) 6.5 1.53 (6) 7.1 0.89 (t) 7.4 1-isopropoxy-tagitinin F iPrD HO "" 41-butoxy-tagitinin F BuO HO "" '1H-NMR ........................................... ................................ .................................................. ......................... 4.07 (dd) 10.6 / 6.5 2.03 (ddd) 2.45 12.4 / 11.0 / 1.5 (dd) 12.6 / 6.3 5.54 (m) , 46 (m) 4.09 5.58 (dt) 11.5 / 4.7 1.66 (dd) 14.8 / 4.7 2.16 (dd) 14.7 / 11.5 5.66 (d) 2.2 6.11 (d) 3.0 1.48 1.76 (t) 1.9 2.38 (7) 7.0 0.99 (d) 6.9 1.01 (d) ) 6.9 3.81 (d) 1.3 3.48 (t) 6.5 1.50 (m) 1.35 (6) 7.4 0.90 (t) 7.4 1-ethyl- mercapto-tagitinin F HO O 1H-NMR 5 mv ti The .j. 6_0 1.01 dt 7.4 1..54 s 1.78 .c1d:] 5, 4.7 1..78 t 1.7 2 ... 04 d] .14 ... O.,: 11..5 2.11 m 2 ... 38 m 7.O 2.43: dd] 2 62 2.0.2 m 12.6.5.3 3.89 1.3 4..11: m 5..43 m 5.55 5.8 1.1 7 '5.60 to 2 ... 2 6.11 13 C RMIV: 176.8; 170.9; 142.5; 138.1; 129.1; 123.4; 105.1; 85.0; 76.8; 72.6; 53.0; 50.7; 46.8; 37.9; 35.2; 27.7; 27.2; 23.4; 19.7; 19.3; 15.9. 1-hydroxy-3-ethylmercapto-tagitinine F HO 42 EtS.H-NMR5 hetl (in: Type -J 0, gD d 6.9 d 1.:20 t 7..6 1.45 s 1:, 7g dO & a, 11 ..0 1:91 t 1.9 2.27 14..8 2.3D 7..3 2.5.3 2.70 dO 14 ... g, 5.7 3.43 40.4 dd 10..4-, 5.0 4.23 5.35 set 2.7 5.61 '10 ... g, 4.5 5.65 d 2.5 5.67 dq 2.8.a 512 d 13C-NMR: 176.5, 170.2, 142.1, 138.3, 128.9; 122.7, 96.6, 88.7, 78.5, 77.7, 72.3, 49.5, 48.4, 41.4, 34.9, 26.5, 24.6, 21, 5, 19.4, 19.0, 14.8.

1,3-di-trichloroethoxy-tagitinin F 43 CC13CH2O 1H-NMR: 44 1 ... 58 s 1_85 dd 14..5, 11.0 1.8D t D8 dd 8.8.,. 4.7 2.41 '7_0 2_69 dd 2.64 dd 15_1, 1.6 19D d 11, G 4_13 dd 1.4 417 d 11.7 .4,2D d .7 5.62 10.3, 4.3 d 2_5 5.14 d 2.8 o 45 htl the ppp Type I.05 6.0. 1.05 d 6 ... 6 1..40 1..96 t 1.6 2.2 3: qd 2..3.9; tai 1.5.a to 3.8 2 ... 49 .3.54 m. 4..10 d 16.7 4.22 Il: 0 5a1 ddd 4.8: 17, 1..3 5.72 dq & 2 5 577 d 2 ... 5 5..78 6.0. 5.8.1 - 6.15 2.8 6..60 .5.7 1-hydroxy-3-trichloroethoxy-tagitinin F HO CI3CCH2O- 1H-NMR: pet: (ppm Typa 1. 00 5.9 1.02 d .49 s d .. 14.5., 47 1.82 t 1.g 2..17 .dd 12.9,1.0.4 2.40 m 7.0 2.55 dd 13.26.9 3.43 5..G 183 1G.7 4.23 167 4 .25 4.33 ddd 10.4, 6.G 5. G 5.44 563 II 3 4.6.6.3 d 2.2 5'itq 72 2.8, 1.5 613 d ... 8.46 3-trifluoroethoxy-tagitinin F H-NMR: 3hel (ppm Type z.): 0.5 d 65 1 .06: d 6 .. {l: 37 st t.6 2,2D d: 1 5.8, 4.7 dd 3.sg 2,4E: m 7..0 3.55 m dq 11: 7, 4.04 1..T , ddd 5.0, 3.5.1 5..72 m - 573 6.0 5.76 m 5.77 d 2 ... 5 6.15 d 2.8 6..54 .5.7 1-hydroxy-3-trifluoroethoxy-tagitinin F H-3g2: 47 Dtel (ppm Type d (Hz 0.93 d 73. d .'Ei.TD 1.45 s 1.73 t .e.3 235 t4.2 2.33 m 6.9 2.59 14.88 2.87 7.9 3.69 12.0, 1.95 .6 4 4 05 12'.C .: 4m 534m - 5.61 ddd 10.3.5.1 3.8 5:63 2.5 524 6.13 d 2.3 1,3-di- (2-fluoroethoxy) -tagitinine F FCI-12CH20 F CH2CH20 '1H - NMR: 48 D 'el (dm Type 1.00 6.9 1_02 d 1.73 dd 4.8 1_74 t .6 2.09 m 2.49 7.0 dd 12.8a 3., S9 m 3..69 m 4.07 dd 1114. The .4_45 m 4_55 m 5.4.4 m 5_55 d 2.5 5.79 5.12 HO "'tgll ~ 1r? ~ Type 0.93 e 1.DJ 147 - .72 ti` 1.4. 4.7 f.7: t ... 2 ..; 2. äd i2..8, C.. 1..5 2..2.4 d4.! , 11.5 37 UT: 2.48 12: 6. & 3 3. .83, .. 3. 4.1 c1d .5 4.54 1: D 4..58 1.2.0 5.40 m _ 5.55 u 5:60. C ~ 11 .3` 4.7 5.6 2 .. 6.1 2.5 7.3..3 m - 1.3. Addition of morpholine to tagitinin C To a solution of tagitinin C (35 mg, 0.10 mmol) in dichloromethane (500 μL) an excess of morpholine (500 μL) is added. After 5 minutes in the dark, the reaction mixture is concentrated and the excess morpholine evaporated. The residue is filtered on an SPE column of neutral alumina III (eluent: cyclohexane / ethyl acetate 2/8 followed by pure ethyl acetate). Fractions containing 1-morpholino-tagitinin F and 13-morpholino-tagitinin F (6 mg, 13%) and fractions containing the tagitinin C adducts (25 mg, 58%) are obtained. The latter purified by preparative HPLC (eluent: cyclohexane / ethyl acetate / THF 3/7/3%), lead to 1113-13-morpholino-Tagitinin C (13 mg) and to a 55/45 mixture of 1113- 13-Morpholino-Tagitinin C / 1113-1,13-Didimorpholino-Tagitinin C (8 mg). Tagitinin C subjected to the same protocol for 24 h gives 1113-1,13-di-morpholino-tagitinin C with 83% yield. 49 50 -Morpholino-tagitinin F o - HO 10 1H-NMR: ile.1 (ppra Type d 7.a3 1.53 - 1.7'G i4 .Z 1ä7 1T 2.0: 7 - 2.3.3 77 tld -11115..3 33Z t 4.5: 3.77 d ç 4.07 m: 5.45 5..53 m 5.64 5a1I d 1.8, 13 C-RM1V: 176.5, 170.8, 142.7, 137.9, 128.7, 123.1, 103.7, 84.0, 76.5, 73.7, 72.2, 67.5 (2C) 54.2 (2C); 50.9; 43.3; 36.7; 34.9; 29.5; 22.9; 19.5; 19.0 13-Morpholino-tagitinin F 1H-NMR: 5 iel (p Type d 1 ... 07 .'6S, 1 .G7 d 1..32 s 1..34 t 1.4 215 m 222 m 2.48 3 ... 08 3.6D t 4.i 3.G5 s 5..42 t 3..6 5.6D d 5.7 5..72 dq 7..4, 1..4 5.08 7: 3, 5.42 d 5.7 13 C-RM1V: 178.2, 176.6, 141.4, 140.6, 130.9, 128.1, 109.4, 88.4, 76.1, 70.0, 67.7 (2C), 55.2, 54.0 (2C), 46.0, 44.1, 38.1, 35.2, 31.5, 21.1, 19.0, 19.2, 1113-13, Morpholino-tagitinin, C OH, 1H-NMR, $ 515, hr pRI Type J (Hz) 1: 455 d 33 141 s, 1.99 d ç 2 .zt 5 22 2. 2 1 2 41 1 ~ K ç @ 2. d 13: 1 .. 4 to 32 3.45 s - 3.51 m - d. 5. dd $% 2217 5.20 9.1 i 5.23 173 d $ T9 ° 3 C-NMR: 198.2; 178.3; 176.7; 161.4; 139.5; 138.1 130.4; 77.9; 72.5; 70.9; 67.7 (2C); 54.4 (2C); 54.2 48.1; 45.0; 39.0; 35.1; 29.6; 19.9; 19.1; 18.8 1,13-Di-moro holino-tetinine C ~ oo H-3g2: 1.05 (d, J = 3.6, 3H); 1.07 (d, J = 3.6, 3H); 1.46 (s, 3H); 1.72 (d, J = 1.5, 3H); 1.81 (dd, J = 12.7 and 3.3; 1H); 2.10

(d, 2H); 2.28 (m, 5H); 2.42 (m, 1H); 2.58 (dd, J = 13.1 and 4.3, 1H); 2.94 (dd, 1H); 3.12 (t4, 1H); 3.57 (m, 4H); 3.71 (4t, 1H); 3.74 (s, 1H); 5.38 (m, 1H); 5.61 (44, 1H); 5.63 (dd, 1H). 13 C-NMR: 19.01; 19.17; 23.15; 30.77; 36.05; 36.62

39.74; 43.50; 47.84; 54.98; 55.78; 69.12; 73.02 52, 74.01; 78.42; 87.81; 129.03; 141.83; 170.57; 176.39; 198,20.

1.4. Preparation of 113-methoxy-13-morpholino-Tagitinin C / F A solution of morpholine (175 μL, 70 eq.) In dichloromethane (1 mL) is added to a solution of F-3-methoxy-tagitinin ( 10 mg, 0.02 mmol) in dichloromethane (500 μL). After 5 min at room temperature, the reaction mixture is concentrated and the excess morpholine evaporated. After purification on an SPE column of silica gel (2 g, eluent: Cyclohexane / ethyl acetate 7: 3), 8 mg of 13-methoxy-13-morpholino-tagitinin C / F ((1/1)) is obtained. in the NMR solvent) (Yield 85%). 113-Methoxy-13-morpholino-tagitinin C / F Open Form (C) 1H-NMR: 1.0-1.06 (m, 6H), 1.10 (s, 3H), 2.62 (dd, J 16.7 / 6.0, 1H), 2.93 (dd, J 16.7 / 4.1), 2.97 (d, J 9.1, 1H), 3.81-3.87. (m, 1H), 5.65 (d, J 9, 1H), 5.51-5.57 (m, 1H), 6.10 (d, J 7, 8, 1H) 13C-NMR: 46, 08, 47.64, 83.7, 75.8, 71.2, 133.4 Mass: 490 (M + Na) is (467 + 23) Closed Form (F) 1H-NMR: 1.0-1, Δ (m, 6H), 1.42 (s, 3H), 1.76 (s, 3H), 3.08 (td, J 10.4 / 4.7, 1H), 3.68 (dt, J); 10.5 / 2.7, 1H), 3.99 (dd, J 10.5 / 6.3, 1H), 5.42-5.47 (m, 1H), 5.51-5.57 ( m, 1H), 5.61-5.66 (m, 1H) 13 C-NMR: 38.73, 47.3, 87.6, 77.8, 71.5, 129.1. Mass: 490 (M + Na) or (467 + 23)

1.5. Other additions of amines on tagitinin C The procedure described in paragraph 1.3. concerning the addition of morpholine to tagitinin C was reiterated by replacing morpholine with other amines. The following derivatives were thus prepared: 13-piperidino-tagitinin C 1 H-NMR: 1.03 (d, J 6.9, 3H), 1.05 (d, J 7.3, 3H), 1.41 ( s, 3H), 1.55 (m, 6H) 1.90 (d, J 0.9H), 2.18 (m, 2H), 2.22 (dd, J 13.1 / 10.6 , 1H), 2.36 (m, 1H), 2.41 (dd, J 13.9 / 6.9, 1H), 2.53 (m, 2H) 2.59 (dd, J 13.1); 4.3, 1H), 3.21 (m, 2H), 3.46 (s, 1H), 5.45 (d, J 9.5), 5.50 (ddd, J 9.4 / 7, 2 / 1.7, 1H), 6.20 (dq, J 9.1 / 1.6, 1H), 6.23 (d, J 17.3, 1H), 13C-NMR: 18, 8, 19 , 1, 19, 9, 29, 6, 54, 2, 54.4 (2C), 67.7 (2C), 70, 9, 139.5, 161.4, 176.7, 178.3, 198 2. Mass: 456 (M + Na) is (433 + 23)

1,13-Di-piperidino-tagitinine C 6.87 (d, J 17, O, 1H). 35, 1, 39, 0, 45, 0, 48, 1, 72, 5, 77, 9, 130, 4, 138, 1, 1H-NMR: 1.45 (s, 3H, Me-14) , 1.74 (s, 3H, Me-15), 2.88 (dd, J 12.0 / 6.0, 1H, H-1), 3.03 (td, J 10.3 / 4.6 , 1H, H-11), 3.69 (dt, J 10.6 / 2.9, 1H, H-7), 5.39 (m, 1H, H-6), 5.57 (m, 1H). , H-8), 5.61 (m, 1H, H-5) Mass: 541 (M + Na) is (518 + 23)

13- (N-Methyl-piperazino) -tagitinine C 1 H-NMR: 1.50 (m, 6H), 1.41 (s, 3H), 1.90 (s, 3H), 2.19 (s, 3H); ), 2.22-2.26 (m, 1H), 2.35 (hept., J 7.0, 1H), 2.38-2.46 (m, 2H), 2.24-2.46 (m, 4H), 2.57 (dd, J 12.8 / 3.9, 1H), 2.66-2.93 (4H), 3.13-3.22 (m, 2H), 5, 42-5.49 (m, 2H), 6.17-6.21 (m, 1H), 6.23 (d, J 17, 5, 1H), 6.86 (d, J 17, 2, 1H) ). 13C-NMR: 18, 85, 19, 09, 35, 06, 39, 68, 39, 68, 45, 06, 48, 12, 68, 77, 70, 89, 72, 47, 77, 83, 130, 40, 138.15, 161.46, 168.53, 176.65, 178.35, 198.20. Mass: 456 (M + Na) is (433 + 23)

13-dimethylamino-tagitinin C 1 H-NMR: o 5 gtl (ppm pe Y y 3 h 'Ty') IL: 93 6_9 1.05 ti.9 1.41 s 1..90 0: 9 2.37 m 3.15 m 5.37 ddd 8.8 ... 5,545,9_5 6,221 9.1, 1_3 8.23 6..89 7.0 13 C-RM1V: 198.1; 178.2; 176.7; 161.3; 139.4; 138.1; 130.5;

77.7; 72.5; 70.8; 55.7; 48.1; 45.8 (2C); 44.9; 39.9; 35.1; 29.5; 19.9; 19.1; 18.8 1-Dimethylamino-tagitinin F 56 HCl 1H-NMR: A! 'Type- 0.98 5.9 1.01 d E 1.53 1.71 d! 14: 4.9 1.78 t 1 ... 7 42. 1..3 2..32 m - 2.38 m 7 ... O 2:76 11..85 .. s 4.07 m 5 ... 47 5.53 3.4 ,. 5.02 1 .7 ... 4.7 5.56 2.2 aie d 2.5 13 C-RM1V: 176.5; 170.8; 142.7; 137.9; 128.6; 123.1; 103.6; 84.2; 76.5; 75.0; 72.4; 50.8; 46.2 (2C); 44.7; 36.5; 35.0; 29.1; 22.9; 19.5; 19.0. 1.6. Preparation of 1-N-hydroxylamino-tagitinin C Hydroxylamine (20.85 mg, 0.3 mmol, 10 eq) was dissolved in distilled water (0.1 mL). The pH of the solution is adjusted to 6.5 by addition of a saturated solution of Na 2 CO 3. This solution is added at 0 ° C (ice bath),

a solution of tagitinin C (10 mg, 0.03 mmol) in dioxane (0.5 mL). After 5 min, the ice bath is removed and the reaction mixture is allowed to return to room temperature.

After 30 min, the reaction medium is diluted in cyclohexane (0.3 mL) and directly deposited on a SPE column of neutral alumina III surmounted by a layer of celite (0.5 cm)

(eluent: cyclohexane / ethyl acetate 3: 7). The evaporated filtrate is again deposited on an SPE column of neutral alumina III (eluent: cyclohexane / ethyl acetate 1: 1). We

isolates from tagitinin C and a mixture of products whose purification by HPLC (high liquid chromatography

performance) (YMC-Pack SIL 5) Gym, 120 Å, 4.6x250 mm, cyclohexane / ethyl acetate 1: 1, 1 mL / min) leads to 100 μg of 1-N-hydroxylamino-tagitinin C.

1-N-Hydroxylamino tagitinin OH NMR OCOiPr 1 H NMR: 1.05 (s, 3H), 1.10 (s, 3H), 1.35 (s, 3H), 1.75 (ddd, J 16.1) / 7.6 / 1.1, 1H), 1.9 (s, 3H), 2.3 (dd, J 16.0 / 2.0, 1H), 2.40 (dd, J 14.7). / 9.7, 1H), 2.5 (Sep, J 7.0), 2.6 (s, 1H), 2.75 (dm, J13.9, 1H), 2.95 (m, 1H) , 3.4 (m, 1H), 4.0 (s, 1H), 5.35 (m, 1H), 5.45 (dd, J 8.5 / 1.3, 1H), 5.8 (m, 1H), d, J 3.2, 1H), 5.95 (t, J 9, 0, 1H), 6.05 (d, J 3, 1, 1H), 6.65 (d, J 5, 6, 1H). ). Mass: 404 (M + Na) or (348 + 23) 1.7. Preparation of 13-N-benzylhydroxylamino-tagitinin C and 1,13-di-N-benzylhydroxylamino-tagitinin C N-benzylhydroxylamine hydrochloride (19.04 mg, 0.12 mmol, 4 eq) is dissolved in distilled water (0.1 mL) and adjust the pH of the solution to 7 by addition of a saturated aqueous solution of Na2CO3. The latter is added to a solution of tagitinin C (10 mg, 0.03 mmol). After 5 min at room temperature, TLC of the reaction mixture shows that the reaction is complete.

The dioxane is evaporated and the residue is then filtered through a silica gel SPE column (eluent: cyclohexane / ethyl acetate 3: 7). The filtrate is evaporated and the products are purified by HPLC on the Waters Spherisorb ODS1 column (5 μm, 4.6x250 mm) eluted at 1 ml / min by the linear gradient water / acetonitrile 90:10 to 10:90 in 30 min, followed of isocratic elution with the water / acetonitrile system 10:90 (5 min). 1 mg of 13-N-benzylhydroxylamino-tagitinin C (yield 7.8%) and 1 mg of 1,13-di-N-benzylhydroxyaminotaginin F (yield 7.6%) are obtained. 13-N-benzylhydroxylamino-tagitinine C 10

1H-NMR: 1.10 (m, 6H), 1.45 (s, 3H) 1.91 (s, 3H), 1H) 2.35 (sep, 1H), 2.43 (m, 1H) ), 2.54 (m, 1H), 1H) 3.35 (m, 2H), 3.56 (se, 1H), 3.77 (m, 1H), 5.49 (m, 1H), 6.20 (m, 1H), (m, 1H), 6.25 (d, J 17, 3, 1H), 6.85 (d, 1H, J 17.3), 7.20-7.40 (m, 5H). 13 C-NMR: 18, 8, 19, 1, 19, 9, 29, 6, 35, 1, 45, 2, 48, 1, 56, 2, 65.3, 70.9, 72.6, 77 , 9, 128.1, 129.2, 130.0, 139.3, 130.4, 138.2, 160.9, 198.

Mass: m / z 494 (M + Na) is (471 + 23). 1-13-N-benzylhydroxyamino-tagitinin F cH2c6H5HuNi / 1.90-2.0 (m, 3.03 (d, J = 5.47 (m, 1H) 1H), 6.27 (m, HO 1H-NMR: 1.1 (m, 6H), 1.5 (s, 3H), 1.75 (s, 3H), 1.95 (m, 1H), 2.15-2.25 (m). , 2H), 2.35 (dd, J 6.0 / 6.7, 1H), 2.52 (sep, J 15, 0.1H), 2.7 (m, 1H), 2.85 (dd, J 9.1 / 4.4, 1H), 2.95 (dd, J 8.3 / 4.4, 1H), 3.4 (dd, J 5.1 / 6.7, 1H) , 3.6 (d, J 13, 5, 1H), 3.8-3.95 (m, 5H), 5.35 (m, 1H), 5.55 (m, 2H), 5.85 ( s, 1H), 5.95 (s, 1H) .13C-NMR: 19.2, 19.3, 23.4, 28.6, 35.1, 36.4, 42.5, 43.5, 50.0, 61.8, 64.4, 65.8, 72.5, 74.3, 78.0, 85.0, 104.3, 127.5, 130.5, 142.1, 177.5 Mass: 617 (M + Na) or (594 + 23).

1.8. Reduction of Tagitinin C In a bicolor topped with a coolant and containing a solution of CeC13.7H20 (2.67 g, 7.18 mmol) in anhydrous methanol (8 mL), a solution of tagitinin C ( 624 mg, 1.79 mmol) in anhydrous methanol (10 mL) then NaBH (OMe) 3 (929 mg, 7.26 mmol) in one portion. The mixture is stirred at room temperature (RT) for 5 minutes. After addition of water (50 mL), the pH is adjusted to neutrality with 4% aqueous hydrochloric acid solution. The mixture is extracted with ethyl acetate. The combined organic phases are dried with anhydrous Na 2 SO 4, filtered and concentrated in vacuo. After purification by CMP (gradient: cyclohexane / AcOEt 5/5 to 2/8 in 45 min), 30-hydroxy-tagitinin C (18%), 1,2-dihydro-3 are isolated in order of elution. hydroxy-tagitinin C (12%), 3α-hydroxy-tagitinin C (52%), and 11,13-dihydro-3-hydroxy-tagitinin C (18%). 30-hydroxy-tagitinin C Major conform 72% 1H NMR:> 3pm1 Type u: Fz` 1. ~~, ~ - 1 .. `'2 d 1.23 s - 1., ~ 2, ... 6 2 .. 5'2 '~~ tt. iJ: 3.2 3. E4 s -? .Sg.5 5 ... 25 ~? 3 5.64 t ~ ..8 5 6 iAt 15..g. 5 ... 78 .2.B 5. 9? 15..3: 25 5.12 e 3.5 13 C NMR: 177.5; 170.6; 147.6; 132.6; 131.4; 126.3; 122.1; 72.9; 75.0; 71.1; 29.5; 25.3; 19.2; 19.0; MS: m / z 373 (M + Na). 69.6; 51.2; 43.4; 34.9; 20 10 Minor conform 28% H NMR: (ppm Type d 1: 0.3 d 7.3 1.34 1.t - 2:05 dd 13a7, 4.6 2.21 dd 142, 2.35 sr> t 3 to 15 s 4.4 6.9 51 5.47 d 7.3 579 d 5.84 nn .17.113.3 6.19 d 1.3 13 C NMR: 176.5, 171.7, 142.5, 140.9, 134.1, 128.0, 123.3, 76.9, 75.6, 74.3, 49.3, 45.4, 34.9, 32.0, 23.7, 19.1 (2C); : m / z 373 (M + Na), 1,2-dihydro-3-hydroxy-tagitinin C 1 H NMR: IMTMMMMM ##! OEMMMMMM 1.41 (dddd) 1.80 14.7 / 9.5 / 3.6 / 1.6 1.69 1.90 4.28 (q) 4.7 5.43 (dq) 9.3 / 1.2 6.23 (dd) 9.1 / 3.5 3 , 31 -5.00 5.36 (ddd) 10.8 / 4.6 / 3.1 61 OCOiPr 5, 66 (dd) 14.5 / 10.4 2.74 5.68 (d) 2.2 6.15 (d) 2.4 1.19 1.68 (d) 1.3 2.38 (7) 7.0 1.01 (d) 6.9 0.99 (d) 7.3 3, 48 (d) 4.4 2.73 C NMR: 128.1, 123.1, 75.8, 74.8, 74.3, 49.3, 40.3, 37.0, 35.1, 32.3. , 1, 30.9, 23.8, 19.3 (1C).

MS: m / z 375 (M + Na, 352 + 23). 3a-hydroxy-tinine tag C

OH 0 CH; H3C / 4 CH3 Ho,.: ,,

## EQU1 ## where: ## STR2 ## where: ## STR1 ## : 3.2 3.20 4..7 3..55 s 5.01 m 5..10 1: 9.8 5 .. 2 m 5! 9 d G.1 5.55 d $ 15 5.73 dd 15.4.9.a G..14 ZI. 2 62

63 13 C NMR: 177.5; 139.3; 132.5; 122.2; 122.0; 75.1; 73.6; 70.9; 69.2; 51.4; 43.5; 34.9; 29.0; 20.7; 19.1; 19.0 MS: m / z 373 (M + Na) 11,13-dihydro-3-hydroxy-tagitinin C 0 0/2.: 1H NMR: 3h-gt1f..appel Tee 1.1 5.9 1.11 d 6.9 1.29 d 6.9 1.29 s .I.135 d 15.4 16 s - 2AI m 2.4 GT-lt 2..59 s 6.6 322 d 4A 179 s 4.97 t 10.2 5.01 5:07 9.8 5 5.75 13 C NMR: 179.2, 177.6, 148.9, 132.5, 122.2, 74.9, 73.5, 70.9, 69.3, 54.2, 43.2, 37.3, 34.9, 28.9, 20.5, 19.1 (2C), 15.5 MS: m / z 375 (M + Na) The alcohols 1,2-dihydro-3-hydroxy-tagitinin C and 11,13-15 dihydro-3-tagitinin C were oxidized by manganese dioxide according to the following protocol: a solution of the allyl alcohol (10-15 mg) in dichloromethane (0.5-1 ml) is added MnO2 (10 eq.Ol Mass, ie 100-150 mg) .The resulting suspension is stirred at RT under Nitrogen atmosphere (the reaction is followed by thin layer chromatography) Once the reaction is complete, the reaction medium is filtered on celite and then the celite is washed with dichloromethane. chromatographed on SPE column of silica gel.

F / C 1,2-dihydro-tagitinin ((8/2) in the NMR solvent) Majority form (F) 1H NMR: Yield 17; r:? .0 1.61 '61 5 .. 144 s 1.7 t 1..8 1 .. 4 Id 14.6,: 5., Û ..t r7 - 2.02 r7 2,12 7 - 2. E ?? - 2 7.0 167 d 0.6 4.5)) ti: • tt ..1 ... 2..4: F}. 5.6 C, 2.4 NMR: 176.5; 170.8; 143.5; 138.2; 128.4; 123.1; 107.1; 83.6; 76.6; 73.1; 50.7; 41.3; 39.1; 38.1; 35.0; 28.4; 22.7; 19.4; 19.0 MS: m / z 373 (M + Na), 13-dihydro-tagitinin C 1H NMR: Dh, p. 1t `vo L fi .. ~ 1.41 2aW: m 2. 1: 't] 2.43 2 47 e .O 2. .0 d 17.0 13 NMR: 198.1, 180.0, 177.2, 161.0, 141.7, 138.3, 130.5, 77.7, 72.5, 72.4, 51.4, 47.8, 39.7, 35.0, 27.8, 20.2, 19.2, 19.1, 17.6, SM: m / z 373 (M + Na) 1.9 Enzymatic hydrolysis of tagitinin C In a 1.5 ml eppendorf tube containing tagitinin C (10 mg, 28 μmol) solubilized in dimethylsulfoxide (DMSO) (10% vol. pL), a borate buffer solution (pH 8, 300 μL) is added, the crude porcine esterase of the liver (1.03 mg, SIGMA 026K7029) is added to the whitish emulsion formed and the mixture is stirred for 24 hours at room temperature. After 24 hours, the same amount of enzyme is added and the stirring is continued for 24 h, the enzyme is then denatured by stirring in the dark at 300 rpm. addition of a solution of butanol / acetonitrile (vol / vol 1/1, 400 μl) After evaporation to dry the mixture, the residue is added 1/1 butanol / acetonitrile (0.5 ml). After sonication and centrifugation, the supernatant is transferred to a flask.

The operation is repeated until the tagitinol C is exhausted. The combined extracts are evaporated to dryness and the residue is deposited at the top of the column of silica gel SPE (eluent: cyclohexane / ethyl acetate gradient 5/5 to 10 / 0. Tagitinol C (5 mg), 1R-hydroxy-tagitinin F / C (resulting from the addition of water to tagitinin C), is obtained in order of elution, respectively, of tagitinol C (2 mg 25% overall yield, 51% relative to the Tagitinine C consumed) and 1R-hydroxy-tagitinol F / C.

Tagitinol C: 1H NMR: 3h 1;:., Pro Type-? 'i _43 s - 4.87 1..5 .2.'0: i 14. rt 3 2.2' 3.3 5.5 .w5 quin 7.1 537 cf. a., 1.4 5.77 l j.% 5.9D 5 5. 2 2.1 6.23? U 6:87, 16.8 13 C NMR: 199.1; 171.3; 162.1; 139.5; 138.7; 130.3; 123.2; 77.0; 73.8; 72.4; 52.9; 49.7; 29.2; 19.8 113-hydroxy-tagitinol F / C (ratio 1/1). OH (in equilibrium with open form not shown) H NMR (closed form) 1H NMR (open form) 5H (ppm) Type 5H (ppm) Type 1.12 s 1.37 s 1.76 d 1.80 m 1.80 m 1.90 d 2.03 m 1.94 m 2.20 - 2.52 dd 2.41 dd 2.78 dd 3.43 m 3.16 q 3.82 q 4.14 m 4.24 m 4.19 t 4.31 t 5.20 dd 5.37 m 5.74 d 5.51 m 5.81 dd 5.69 d 6.23 d 6.17 s When Tagitinin C, used in hydrolysis, contains traces of tagitinin F or 1α-hydroxytagitinin F, the following products are also obtained.

Tagitinol F: H3C 68 H NMR: $ q & p} 1.32 1 ..82 2: 2.25 $! $ S 3.91 5.59 Ç

5.91 5 .. Type J 6 9 - t! 3] æy 35 15.63.7 m s 14 d 6: 9.1 7 d this m d 37 13 C 3g 2 = 141.2; 131.6; 127.5; 123.0; 101.0; 76.6 (2C); 75.1 (2C); 65.6; 50.1; 48.3; 31.3; 21.1-Hydroxy-tagitinol F H0 H 3g 2: 6.18 (d); 5.71 (d); 5.51 (m); 5.23 (m); 4.35 (m); 4.19 (m); 4.02 (d); 3.92 (m); 2.98 (m); 2.51 (dd); 2.20; 1.76 (d); 1.74 (m); 1.39 (s). NMR: 141.61; 129.40; 122.53; 78.01; 76.23; 70.63; 52.34; 46.19; 43.30; 22.56; 22.39. Furthermore, the use of methanol as a co-solvent makes it possible to have access also to 13-methoxy-tagitinol F / C. In addition, chemical hydrolysis of unprotected tagitinin C was performed by methanolic sodium hydroxide to yield 1,3,13-trimethoxy-tagitinin F. 1,3,13-trimethoxy-tagitinin F. Trimethoxy-tagitinol F MeO "" 1H NMR: titrated Tee J Hz .1.02 s .tld 2.2 1.6 2.4_.1 .7 2.07 m. 2.6.1 ddd 16.1, 7.2a 2.2 2 ... 67 ..2, 57, .6- 2.99 s 3.10 ddd 11.0, 7.5a 7.3 3..32 3.36 s 3.44, d, d: 2.8 3..45 d 1.9 3.5 dd 9..8, 5.0 3.64 3.8 .4..85 7.6.,. 2.2 5.17 m. 6..08 m. 1.10. Preparation of 3α-hydroxy-tagitinol C and 33-hydroxytagitinol C

at. Enzymatic route: To a solution of 313-hydroxy-tagitinin C (136 mg, 0.39 mmol) in a DMSO (0.28 mL) / methanol (0.19 mL) was added the borate buffer (4.2 mL of a solution). mM, pH 8) then the crude porcine esterase of the liver (20 mg, SIGMA 026K7029). The suspension is maintained at RT, with constant stirring at 300 rpm for 24 h, the pH being maintained at 8. After 24 h, 20 mg of enzyme are added and stirring is continued for 24 h. The enzyme is denatured by treatment with a 1/1 butanol / acetonitrile mixture and sonication. After treatment as above, the dry extract is chromatographed on an SPE column of silica gel (gradient: cyclohexane gradient / ethyl acetate 6/4 to 10/0), giving 25 mg of 3α-hydroxy-tagitinol C (yield overall 23%, 47% relative to the hydrolysed substrate) and 70 mg 3a-hydroxy-tagitinin C. 3a-hydroxy-tagitinol C = OH 1H NMR: 4 &, n: AJ df 439 - # 36 28 21 & 7 2.m & fa, d d d d d d d 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1; 148.3; 139.5; 138.2; 132.0; 122.8; 121.9; 75.8; 73.7; 71.2; 65.9; 54.2; 46.3; 29.3; 20.7 Mass: m / z 303 (M + Na) Under the same conditions, 3I3-hydroxy-tagitinin C, leads to 3I3-hydroxy-tagitinol C with a yield of 14% relative to hydrolyzed 3I3-hydroxy-tagitinin C . 313-hydroxy-tagitinol C OH 1H NMR: Position Conform 1 Conform to 2 1 5.70 5.73 2 5.77 5.78 3 4.52 (if) 4.46 (t, 6.6 Hz) 5 5.21 (d, 9.5 Hz) 5.08 (d, 7.0 Hz) 6 5.51 (t, 9.3 Hz) 5.33 (d, 7.0 Hz) 7 2.96 (m) 3.08 (si) 8 4.13 (m) 3.97 (dtd, 10.5, 5.2 and 2.4 Hz) 9 1.99, 1.68 (dd, 15.3 and 2.19 (dd , 14.3 and 10.7 1.5 Hz) Hz), 2.02 (dd, 14.0 and 5.2 Hz) 13 6.06 (dd, 3.4 and 1.2 6.9 (d, 1.2 Hz), 5.62 Hz), 5.86 (dd, 3.1 and (d, 1.2 Hz) 1.2 Hz) 14 (Me) 1.29 (s) 1.33 (s) 15 (Me) 1.90 (d, 1.2 Hz) 1.79 (s) 3 (OH) 3.51 (d, 3.4 Hz) 3.35 (d, 6.7 Hz) 8 (OH) 2.87 (d, 4.0 Hz) 2.81 (d, 5.2 Hz) (OH) 2.74 (s) 2.94 (s) Mass: m / z 303 (M + Na) OH b. Chemical way: b1. Formation of 3-Hydroxy-13-morpholino-tagitinin C General Method A solution of 3-hydroxy-tagitinin C (1 eq) in anhydrous dichloromethane (1 mL / 15 mg) is added with morpholine (8 eq). After 10 min at RT, the morpholine and the solvent are evaporated. Chromatography of the residue on a column of silica gel (dichloromethane / methanol 95/5 to 90/10) leads to the corresponding adduct.

Substrate (3-hydroxy-3-hydroxy-11- (3-13-morpholino) -toluene-3-hydroxy-3-hydroxy-3-hydroxy-3-hydroxy-3-hydroxy-11α-13-morpholin-3-hydroxy-3-hydroxy-3-hydroxypropyl hydroxy-11 (3-13-morpholino) -liquidinine C tagitinin C 3a-hydroxy-11a-13-morpholino-tagitinin C 30-hydroxy-110-13-morpholino-tagitinine C 1H NMR: 5: 1, ppri Type Hz) 1 .93 4 25 0 7.3 ä32 s ä82 s 2.29 sä 2..34 sp 7.1 Pr. S. 2.53 43.4 .6 2..89 8.4 2.0 2.99 1 0G.9, 4.3 3.94 s 3:58 m 4.49 t {3..5 5.31 5.41 m - 5.7.9 0 15.7 5.81 17.0, 6.6 NMR: 178.8, 176.7, 141.9, 141.2, 133.5, 127.5, 77.5, 74.8, 71.7, 70.9, 67.6 (2C) 54.3 (3C), 46.7, 44.4, 39.6, 35.1, 32.4, 23.7, 19.2, 18.8;

30-hydroxy-11α-13-morpholinoliniticin C 0-1H NMR: CH 3 CH 3 HG> 3tel (ppm Type, 1.12 1.30 s 1.65 d 454 d: 6 2 dd 1S..g> 237 br.s 24 p! I 2.52 dd 44 2..57 d 3.8 2..73 .3.8 335 45 5.12 m 5 ... 55 1 10.1 5:75 dd 5.D'l del S..g> 2.2: 13 C NMR: 179.1, 178.2, 147.7, 132.7, 131.9, 127.1, 75.2, 73.3, 71.5, 70.2, 67.9 (2C), 57.7, 55.5 (2C), 49.0, 43.7, 42.1, 35.1, 29.8, 25.5, 19.7, 19.3. Mass: m / z 460 (M + Na) 3? -Hydroxy-110-13-morpholinoliniticin ## STR1 ## Conformed to a major 60% 1H NMR: 74.5 hr Type 8.9 1.05 .9 1231 s - 1.8.4 2.93 13.7> 4.9 2.45 sä 2.90 380 m .4 Prof .: a, 5a84, z'3 - 5..41 ddd '10 .'5, 1 D 5iDiD 17 ... G> 7.0 13 C NMR: 141.7, 141.0, 131.3, 128.4, 77.6, 72.1, 71.0

70.9; 48.9; 44.3; 39.3; 32.5; 23.7 Mass: m / z 460 (M + Na) Minor compliant 40%

1H NMR: 75 - = 'ilel (pprl 1.02 1.04 1.20 1.85 1.80 2% 29 2.45 4.85 5.25

5.55 5.65 Typa. d 6 4 6.13: s del 14..G ,. s 1. r. s. dd 7.7, 30 d 0.16: .e ddd 2: 8 dcl 15.4 ,. D .1 .d 1% 5.4 13 C NMR: 142.8; 139.3; 131.1; 126.1; 77.4; 73.8; 71.4 10 71.2; 67.6 (2C); 54.5 (2C); 54.4; 48.1; 42.2; 39.9 35.1; 30.9; 22.0

Mass: m / z 460 (M + Na)

3α-hydroxy-11α-13-morpholino-tagitinine C OH; -, • • • • ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 218 e 7.0 2.84 dt _3.2 2.51 and 2.60 m 337 4: 6 4.78 t DS d P ... 5 5.01 d 15A. 5.04 brs, 5: d 61 g M: 9, NMR: 178.0; 177.1; 148.3; 139.2; 132.9; 122.4; 74.0; 73.6; 70.5; 70.1; 67.5 (2C); 57.0; 55.4 (2C); 48.2; 43.9; 42.4; 34.6; 29.3; 20.9; 19.2; 18.9 Mass: m / z 460 (M + Na) The oxidation with MnO 2 of 3-hydroxy-11α-13-morpholinotagitinine C and 3-hydroxy-11β-13-morpholino-tagitinin C gives access to the derivatives Ila-13-morpholino -tagitinin C and 11β-13-morpholino-tagitinin C, respectively. Lla-13-morpholino-tagitinin C 1 H NMR: 6.91 (d, J = 17.4, 1H); 6.25 (d, J = 16.9, 1H); 6.09 (dd, J = 9.1 and 1, 3, 1H); 5.41 (d, J = 8.8, 1H); 5.11 (ddd,

J = 3.0, 6.2 and 9, 3, 1H); 3.63 (m, 4H); 3.49 (s, 1H); 3.24 (m, 1H); 2.67 (d, J = 7.7, 2H); 2.51 (dt, J = 2.3 and 7.7, 1H) 2.50 (m, 2H); 2.43 (hep, J = 6, 9, 1H); 2.28 (m, 2H); 2.41 (m, 2H); 2.31 (dd, J = 14.0 and 5, 9, 1H); 2.04 (dd, J = 14.1 and 9.5,

1H); 1.91 (d, J = 1.1, 1H); 1.42 (s, 1H); 1.08 (d, J = 7.0,

1H); 1.07 (d, J = 7.0, 1H). 13 C NMR 198.14; 178.71; 177.05; 161.84; 139.48, 139.16; 130.43; 78.52; 74.61; 72.34; 67.61 (2C); 59.27 54.38 (2C); 48.63; 47.09; 44.60; 35.00; 29.07; 19.90 19, 10.

b2. Formation of 3-Hydroxy-13-morpholino-tagitinol C General process:

A solution of 3-hydroxy-13-morpholino-tagitinin C in anhydrous methanol (0.5 mL) is added sodium methoxide at 5 ° C. The mixture is stirred at RT until the substrate disappears. After evaporation of the solvent and chromatography of the residue on a gel column (eluent: dichloromethane / methanol 96/4), the corresponding tagitinol C is obtained.

It should be noted that there is epimerization at the level of carbon

C11 to give only derivatives 11a. NaOMe Substrate Yield (1 eq) mg pmol eq. mg pmol 3P-hydroxy-11p-13- 5.9 109.3 4.3 11.3 25.9 68% morpholino-Tagitinine C 3P-hydroxy-11a-13- 7.1 131.2 9.2 6.2 14.2 28% morpholino-1,1-tetra C 3a-hydroxy-11p-13 7.1.2 4.3 9.3 21.2 25% Morpholino-Tagitinine C 3a-hydroxy-11a-13- 4.7 87.5 6.5 8.8 20.0 85% Morpholino-Tagitinine C 30-Hydroxy-11a-13-morpholino-tagitinol C LJ H NMR: Type 1.30 G 1. .e .; d 14..2 1.89 d 1. 2.00 they 14.5., 5.4 2.95 l; f. 14 t 12.1 2.5'0 2.73 ... id I2.6, 2.8 2.89 d 11.7, 2.a brä lr. . 380 4:53 br. - 5.11 d 95, 1.3 5.51 t 1 G.2 5.63 dd I 535 cI: I 15.8, 2.2 Mass: m / z 390 (M + Na) 3a-hydroxy-11a-13-morpholino-tagitinol C OH 1H NMR: 3W t1 ri Type. .J 1 .. ^ `1_55 1a.8 .. 1..3 2.1 d. ..E w y1 2 .. i8 td 1.2.I..i 6 2.42 br,: _ - 2.45 t 1 .1 2.71 frt. .. - 2.82 ~~ 12.x2. 1 * t1 1 ^. .0 Â. w t. Br. s. -. 9.5 9.5 9.5 9.5 9.5 9.5 9.5 9.5 9.5 9.5 9.5 9.5 9.5 9.5 9.5 9.5 5. 5. 5. 5. 5. 5. RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM RM; 60.3; 58.4; 54.2 (2C); 47.5; 40.6; 29.6; 25.3 Mass: m / z 390 (M + Na) b3 Formation of 3-Hydroxy-tagitinol C A solution of 30-hydroxy-11a-13-morpholino- C and 3a-hydroxy-11a-13-morpholino-tagitinin C (23 mg, 0.05 mmol) in butanol (0.5 mL) is added with methyl iodide (0.5 mL). 120 ° C. for 3 h After dilution with dichloromethane (1 mL), washing with a 10% aqueous solution of bicarbonate and evaporation of the solvents under vacuum, the residue is chromatographed on a column of silica gel (eluent: dichloromethane / methanol gradient 95 / 5 to 90-10) provides 2.3 mg of predominantly 3a-hydroxy-tagitinol C 3 (Yield 10%) 1.11 Preparation of Tagitinol C by oxidation of 3α-hydroxytagitinol C A solution of 3α-hydroxy-Tagitinol C ( 25 mg, 0.09 mmol) d in a 1/1 mixture of dichloromethane / acetonitrile (2 ml) is added MnO 2 (125 mg) and then stirred at RT for 6 h. After addition of 125 mg of MnO 2 r the suspension is stirred for 16 h and then filtered on celite. The celite is washed with ethyl acetate. After evaporation of the solvents, the residue is taken up in ethyl acetate and then filtered again on celite. After evaporation of the solvent and chromatography on a silica column (eluent: 95/5 to 90-10 dichloromethane / methanol gradient), 5 mg of tagitinol C (yield 20%) and 15 mg of 3α-hydroxy-C-tagitinol are obtained, which we recycle. 1. 12. Expoxidation of tagitinin C A solution of tagitinin C (25 mg, 0.07 mmol) in dioxane (4 ml) is added at -10 ° C. to a 30% solution of H2O2 (5 ml). ml) / H2O (5 mL) / Na2CO3 (10mg). After 24 h at -10 ° C, the solution is neutralized with acetic acid, added with water and extracted with chloroform. The organic extract is washed successively with a saturated solution of KHCO 3 brine then dried over anhydrous MgSO 4 and filtered. After evaporation of the solvent, filtration on an SPE column of silica gel (eluent: gradient cyclohexane / ethyl acetate 75/25 to 25/75) then HPLC (eluent: cyclohexane / ethyl acetate 6/4), is isolated (1S, 2R) - (4S, 5R) - (11S) -tri-epoxy-tagitinin C (11.70 mg, Yield 47%), (1S, 2R) - (11S) -di-epoxy- tagitinin C (3.3 mg, Yield 17%) and (1S, 2R) - (11R) -di-epoxy-tagitinin C (0. 61 mg, Yield 1.6%).

The same procedure, carried out at room temperature for 24 hours, leads exclusively to (1S, 2R) - (4S, 5R) - (11S) -triaceoxy-tagitinin C with a yield of 89%. (IS, 2R) - (4S, 5R) - (11S) -tri-epoxy-tagitinine C 1H NMR: el Type Dl & p, 10.0 s - 1% 0.5 d .0T d 5..9: s 1:90 15.1 .. 3.5: 2 .. 'D7 dd 1: 5.0> 1.: 2 .40 spt 243 M .0.9 3.11 2 ... 2 3. 7 4 .7 327 d 5.0 3:54 4 ... 7 3. .5.5 s 3.72 22 5.23 5 5.49 .16 13 C 3M2: 201.9; 176.1; 173.3; 77.8; 70.5; 70.2; 68.5; 65.6; 58.4; 53.2; 48.7; 46.6; 44.5; 34.9; 23.9; 19.1; 18.8; 18.7 1510 (1S, 2R) - (11S) -di-epoxy-tagitinine C 1H NMR: Mt ':% Al Type d 1:07 s 1.03 62 1.93 t .3 1.93 dd 15.4,18 2.23 d 15.3 , 13 2A3 e 5..9 2 i8: t 2.8 113 4 5..0 114 25 3.25 d 5.0 158 s Ml d 25 5: a 3.5.15 5.g2 d 5..0 646 dq 13 C 3M2: 195.9 ; 176.4; 173.6; 139.9; 138.5; 76.9; 70.8; 70.3; 65.7; 58.7; 58.1; 49.1; 48.8; 43.9; 34.9; 24.9; 20.4; 19.0; 18.9 (1S, 2R) - (73) -d-epoxy-tinine tag C 1H NMR: Il o and (w • pm Type J `Hz 1. l8 _. 13 .''- 1., _, V - ' .8 t .d 2.1: pt 7. 2.t.:3 3 ..0 L 2.5 d & G 3_19 & 3, 8 v 2.5 5.33 ': i.8 .'1 5.92 5_E, {{5.4; 1.13 Reduction of (1S, 2R) - (4S, 5R) - (11S) -tri-epoxy-tagitinin C A solution of NaBH4 / MeOH (250 μL, 0.2M) is added to a solution of (1S , 2R) - (4S, 5R) - (11S) -triepoxy-tagitinin C (6.73 mg, 17pmol) in methanol (150 μL) The reaction is stirred for 5 min at room temperature The methanol is evaporated. The residue is deposited at the top of the SPE column of silica gel (eluent: cyclohexane / ethyl acetate 6/4 to 0/10), in order of elution 33-hydroxy- (1S, 2R) - ( 4S, 5R) - (11S) -tripoxy-Tagitinin C, 3α-hydroxy- (1S, 2R) - (4S, 5R) - (11S) -tripoxy-Tagitinin C and 3,12-di- (hydroxy) (1S, 2R) - (4S, 5R) - (11S) -tripoxy-tagitinin C. 333-hydroxy- (1S, 2R) - (4S, 5R) - (11S) -tripoxy-taginine C 1 H NMR: 83 CH Cl & lm Type J {1 s 1 _04 7..0 425 d T.:0 124 s dd 14.6, 401 2.44 spt T.:O 2.91 m 312 d 95 $ .16 d 4: 9 3..26 4 2.7> ec! 84 3.28 4 ... 9 345 3..49 d 2.7 .4.04 t 2..4 5.20; 43.38 ddd 1015.6, 3.2 NMR: 176.2; 77.0; 71.5; 70.3; 64.6; 63.6; 58.4; 49.0; 44.9; 44.0; 34.9; 23.7; 22.1; 19.1; 18.9

3α-hydroxy- (S, 2R) - (4S, 5R) - (IS) -tripoxy-taginatin C C. CH H NMR: type J 0: 417 s 1cg 1.05 d 7..0 1.21 s: 1. S2 ddl 14%! 0.7 '10 .7 dd 14.6, 61 2.43 se 720 2.:D5 t 2 ... 3 2:98 dd 4027 3..0.9 4 .u., 4 315 125 d 2.7 327 4: 9 34 s 3.57 d 5.7 45 ddl .4..78 dd .1 1.8 5.35 ddd 10 5 6. & a RMN: 77.3; 72.7; 71.7; 71.0; 65.1; 64.4; 64.3; 57.4; 48.9; 45.3; 43.6; 35.0; 23.3; 19.1; 19.0; 18.1 1H NMR: 3, 12-di- (ydroxy) - (S, 2R) - (4S, 5R) - (IS) -tripoxy-taginatin C 330 OH H 17.1-t 25 0. cH3 CH 3 85 5 1CI 'çm Type J ", 1. s - 114 d 45 r_ .15 d 1.25 - 1.85 t1; 1 z4.5.1O: 2. ~ 1 14.:x 5.5 2.62: r.1 ] 2.6 m - 4.3 .1 X1.1 115 - 3.2 2: Id 101.1: 7 5.31 - 5.45 3t - 13 C NMR: 177.3, 97.9, 75.2, 73.3, 71.6, 71.0, 67.1, 66.1, 65.3, 64.3; 57.5; 51.5; 46.7; 44.5; 35.4; 23.1; 19.4; 19.2; 18.3 1. 14. Preparation of ester derivatives 1.14.1 Cases of successive protection and deprotection of the C11-C13 double bond and C3 alcohol Synthesis: ## STR1 ## ## STR1 ## (3 RCOC1 pyridine 0. McI / NaHCO3 1OR b.nBu4NF c.BamNO4 or Dess-Martin 10 a- Protection of the alcohol function at C-3: 3-hydroxy-tagitinin C (135 mg, 387 pmol) is solubilized in anhydrous dimethylformamide (DMF) (400 μl), dried using molecular sieve 4 and transferred by cannula into Imidazole (68 mg, 1 mmol) diluted in anhydrous DMF (70 μL) is transferred by cannula; then tert-butyldimethylsilyl chloride (TBDMSCl) (73 mg; 0.48 mmol) and the reaction is stirred at ambient temperature (RT) for 2 hours. The reaction mixture is diluted with ethyl acetate and then washed with water (3 × 30 ml), saturated NaHCO 3 (2 × 30 ml) and brine (1 × 30 ml). The aqueous phase is extracted once with 30 ml of ethyl acetate. The combined organic phases are dried over anhydrous Na 2 SO 4 and the solvent evaporated. SPE column chromatography of silica gel (eluent: gradient cyclohexane / ethyl acetate 8/2 to 0/10 then ethyl acetate / THF 9/1) gives 3a-terbutyldimethylsilyloxytagitinin C (109 mg), 33-t-butyldimethylsilyloxy-tagitinin C (3.4 mg) in an overall yield of 53 as well as in 3-t-butyldimethylsilyloxy-13-imidazolo-tagitinin C (23 mg)

3α-tert-butyldimethylsilyloxy-tagitinin C: 1H NMR: 6.14 (d, J 3.3, 1H); 5.78 (d, J 3. 0, 1H); 5.70 (dd, J 15.5, 9.6, 1H); 5.56 (d, J 15.6, 1H); 5.15 (m, 4H); 3.52 (s, 1H); 3.08 (m, 1H); 2.51 (hept, J, O, 1H); 2.07 (m, 1H); 1.88 (s, 3H); 1.80 (m, 1H); 1.25 (s, 3H); 1.11 (d, J 6.8, 3H); 1.09 (d, J 6.8, 3H); 0.90 (s, 9H); 0.09 (s, 3H); 0.06 (s, 3H). 13 C NMR 139.16; 132.74; 122.21; 121.75; 75.07; 74.91; 70.86; 69.26; 51.40; 43.55; 34.93; 28.84; 26.23; 21.22; 19.14; 19.03; -3.81; -4.73. 30-tert-butyldimethylsilyloxy-tagitinin C: 1H NMR: 6.12 (d, J 3. 4, 1H); 5.90 (dd, J 15.5, 2.2, 1H); 5.78 (d, J 3. 0, 1H); 5.73 (dd, J 15.5, 1.6, 1H); 5.62 (t, J 9.8, 1H); 5.18 (m, 2H); 4.61 (m, 1H); 3.58 (s, 1H); 3.03 (m, 1H); 2.53 (hept, J 6.9, 1H); 2.25 (dd, J 14.1, 10.6, 1H); 2.02 (dd, J 14.1, 4.8, 1H); 1.92 (d, J 1.5, 3H); 1.25 (s, 3H); 1.12 (d, J 6.6, 3H); 1.10 (d, J 6.7, 3H); 0.92 (s, 9H); 0.10 (s, 3H); 0.09 (s, 3H).

1-tert-utyldimethylsilyloxy-1H-imidazolo-tinine C 1H NMR: A @ 4 (ÿ m Tee - '2054 a - EW s - 0.8 atd 63 t} 7 d T3 127 1. 1 1 1.82 2.15 m 2 ]] 261 63 313 ddd 12.5, s2, a3 4.24] 3 .4: 3 4ÆÆ yz 4:, l C! m - 5a7! 10.2 to 95 ç5 d 1 4 S:] 15_6, ga 692 s - J - 7: s 13 C 3g2 = 178.2, 176.7, 150.2, 139.3, 138.9, 133.1, 129.9, 121.3, 120.9, 74.8, 74.7, 70.8, 69.6, 49.1, 45.9, 44.0, 43.7, 34.9, 28.8, 26.2 (3C). 21.1; 19.5; 18.9; -3.8; -4.7. B) Protection of the C11-C13 double bond: The 3a-terbutyldimethylsilylozy-tagitinine C derivative (109 mg, 10 240 pmol) in solution in morpholine (0, 5 m) is stirred at RT for 1 h The morpholine is evaporated under vacuum.

The same operation is carried out with the derivative 30-tert-butyldimethylsilyloxy-13-tert-butyldimethylsilyloxy-13-tetra-13-tert-butyldimethylsilyloxy-holino-tangerine C = H NMR: 6.06 and 5.66 (d / d, J 16.7 / 15.5, 1H) ; 5.99 and 5.51 (dd / dd, J 16.7, 4.2 / 15.5, 9.2, 1H); 5.40 and 5.29 (ddd / m, J 10.4, 5.0, 1.9, 1H); 4.98 and 4.66 (m / d, J 4.0, 1H); 3.60 (m, 4H); 3.20 and 3.17 (s / s, 1H); 3.10 and 2.98 (dd / m, J 7.9, 2.8, 1H); 3.01 (m, 1H); 2.90 (dd, J 8.4, 2.0, 1H); 2.68 (m, 2H); 2.52 (m, 1H); 2.38 (m, 2H); 2.04 (m, 1H); 1.80 (s, 3H); 1.65 (m, 1H); 1.27 (s, 3H); 1.12 (d, J 7.0, 1H); 1.09 (d, J 7.0, 1H); 0.90 (s, 9H); 0.09 (s, 3H); 0.05 (s, 3H). 30-tert-butyldimethylsilyloxy-13-morpholino-tagitinine C: 1H NMR: 5.73 (dd, J 15.5, 9.5, 1H); 5.66 (d, J 15.4, 1H); 5.33 (m, 1H); 5.16 (d, J 9.9, 1H); 5.11 (d, J 10.1, 1H); 5.01 (t, J 10.3, 1H); 3.86 (s, 1H); 3.59 (m, 4H); 3.00 (m, 2H); 2.68 (m, 2H); 2.38 (m, 2H); 2.04 (m, 1H); 1.87 (s, 3H); 1.66 (m, 1H); 1.29 (s, 3H); 1.12 (d, J 7.0, 3H); 1.09 (d, J 7.0, 3H); 0.93 (s, 9H); 0.10 (s, 3H); 0.06 (s, 3H).

c-Hydrolysis of the C8 Ester: A solution of sodium methoxide (447 μL, 2.06 mmol) is added to a solution of 3α-TBDMSO-13-morpholino-Tagitinin C (221 mg, 0.4 mmol) in anhydrous methanol (4.1 mL). After stirring for 6 h at RT, the evaporation of the solvent and purification by medium pressure chromatography (eluent CH 2 Cl 2 / methanol 97/3) gives 3a-TBDMSO-11a-13-morpholino-tagitinol C (176 mg, 90.degree. %). The same operation is carried out with 3I3-TBDMSO-13-morpholino-Tagitinin C. It should be noted that at this stage, C-11 carbon is epimerized to give only derivatives 11a. 3α-tert-butyldimethylsilyloxy-11α-13-morpholino-tagitinol C: 1H NMR: 6.53 (d, J 11.5, 1H); 5.68 (dd, J 15.5, 9.6, 1H); 5.49 (d, J 15.5, 1H); 5.14 (d, J 9.5, 1H); 5.09 (m, 1H); 4.96 (t, J, 10.4, 1H); 3.08 (m, 1H); 3.62 (m, 4H); 2.87 (dt, J 12.0, 2.8, 1H); 2.78 (s, 1H); 2.75 (dt, J 12.8, 2.8, 1H); 2.63 (m, 2H); 2.42 (t, J 12.1, 1H); 2.34 (m, 2H); 2.11 (m, 1H); 1.97 (dd, J 7.4, 3.7, 1H); 1.85 (s, 3H); 1.49 (d, J 14.4, 1H); 1.27 (s, 3H); 0.90 (s, 9H); 0.09 (s, 3H); 0.05 (s, 3H).

90 13 C NMR: 149.30; 138.93; 132.62; 122.37; 76.01; 74.96; 71.46; 67.13; 63.42; 60.18; 58.48; 47.82; 40.11; 29.12; 26.24 (3C); 21.01; -3.80; -4.72. 30-tert-butyldimethylsilyloxy-11α-13-morpholino-tagitinol C: 1H NMR: 6.53 (s, 1H); 5.85 (dd, J 15.5, 1.8, 1H); 5.67 (dd, J 15.5, 2.1, 1H); 5.49 (dd, J 10.0, 10.0, 1H); 5.09 (dt, J 9.7, 1.1, 1H); 4.58 (m, 1H); 3.78 (m, 1H); 3.63 (m, 4H); 2.90 (ddd, J 11.9, 11.9, 2.8, 1H); 2.71 (d, J 12.3, 1H); 2.70 (s, 1H); 2.61 (m, 2H); 2.40 (t, J 2.8, 1H); 2.35 (m, 2H); 2.06 (m, 1H); 2.01 (m, 1H); 1.85 (d, J 1.5, 1H); 1.48 (d, J 1.4, 1H); 1.28 (s, 1H); 0.93 (s, 9H); 0.08 (s, 6H). 13 C NMR: 177.39; 147.42; 132.76; 131.36; 127.15; 76.28; 74.32; 71.73; 67.14 (2C); 63.69; 60.22; 58.54; 54.10 (2C); 47.76; 40.10; 29.82); 26.20 (3C); 24.86; 18.83; -4.37; -4.91.

d- Esterification in the presence of an acyl chloride

(RCOC1): Example with cyclohexane carbonyl chloride:

Cyclohexane carbonyl chloride (26 μL, 197 pmol, 5 eq) is added to a cooled solution at 0 ° C of 3α-t-butyldimethylsilyloxy-13α-morpholino-tagitinol C (19 mg, 39 μmol), pyridine (127 μL; 1.6 mmol, 40 eq) in anhydrous dichloromethane (0.9 mL). After 5 minutes an orange coloration is observed: the chromatography on

thin layer shows a total reaction. The reaction mixture is diluted with ethyl acetate and then washed with water (3 × 20 ml). SPE column chromatography of silica gel (eluent: 7/3 to 4/6 cyclohexane / ethyl acetate gradient) gives 3α-t-butyldimethylsilyloxy-13-morpholino-tagitinyl C cyclohexanecarboxylate (22 mg, 96%).

The other esterified derivatives are prepared according to the same protocol by changing the acyl chloride used, the following steps of deprotection also being carried out according to the protocols described below. 3α-t-butyldimethylsilyloxy-13-morpholino-tagitinyl C cyclohexanecarboxylate 1H NMR: s13 t1 upri T se, F? 2..05 s - ._ 9 s - 1..54 15 ... s 2.5:. ~ 9. 2.7 2. #; s 4.0 _.` 2.7'2 m - 3_, `t 4.1 .9 s .ï1 t 1 t0.2 5.11 '1t .4 5.15 d g: 5 5.55.,. ld 15L8. NMR: 178.6; 149.1; 139.0; 133.0; 122.2; 74.9; 74.8 70.9; 69.4; 67.6 (2C); 57.3; 55.2 (2C); 48.9; 43.9 43.6; 41.8; 30.0; 29.5; 28.8; 26.5; 26.2 (4C); 26.0 21.1, 18.9; -3.8; -4.7. e- Deprotection of the C11-C13 double bond and the C3 alcohol: These two deprotection steps are carried out successively, the order of completion of these two steps not being important. Both possibilities have therefore been realized as described below. Deprotection of the C11-C13 double bond and then deprotection of the C3 alcohol: Step 1: 3α-t-Butyldimethylsilyloxy-13-morpholino-tagitinyl C cyclohexanecarboxylate (22 mg, 38 pmol) is diluted in an excess of methyl iodide (1 mL, 16 mmol, 425 eq). After stirring for 20 h at RT, a white precipitate of 3a-t-butyldimethylsilyloxy-13-methylmorpholinium-tagitinyl C cyclohexanecarboxylate is observed. The excess of methyl iodide is evaporated under a stream of nitrogen and the residue taken up in ethyl acetate and then treated with a saturated solution of NaHCO 3 (2 × 20 ml). The aqueous phase is extracted with ethyl acetate (2 × 20 mL). The organic phases are dried over anhydrous Na 2 SO 4 and the solvent evaporated. Chromatography of the residue on an SPE column of silica gel (gradient cyclohexane / ethyl acetate eluent 10/0 to 4/6) gives 3a-t-butyldimethylsilyloxy-tagitinyl C cyclohexane carboxylate (15 mg, 80%).

3a-t-butyldimethylsilyloxy-tagitinyl C cyclohexane carboxylate 1H NMR: ## STR1 ## wherein: ## STR1 ## 1.40 't - 1..1 _ ~ - 1.70 .a 15.5 _i ?? 1 1.4.? s - 2_ 2.2.9 tt 1.0.0 .t 3.08 dq 8.2, 3.1 33 ti4 4 - 5. t 9..5 5 ... 15 9 .. 5: 5.19 h} ~ .5 15.5 to 5.77 7 .4. 13 C NMR: 176.4; 170.5; 149.4; 139.2; 137.0; 132.7; 122.2;

121.7; 75.1; 74.9; 70.9; 69.1; 51.4; 43.9; 43.6; 29.7; 29.6; 28.8; 26.5; 26.2 (3C); 26.1; 26.0; 21.2; 18.9; -3.8; -4.7. Stage 2: Tetrabutylammonium fluoride (200 μL, 200 μmol, 7eq) is added to a solution of 3-tert-butyldimethylsilyloxy-tagitinyl C cyclohexanecarboxylate (15 mg, 29 μmol) in anhydrous THF (0.5 m). The reaction is stirred for 30 minutes. The solvent is evaporated and the residue taken up in ethyl acetate and then washed with water (3x15 mL) and with brine (1x15 m). The aqueous phase is extracted with ethyl acetate (2 × 30 ml) and the combined organic phases are dried over anhydrous Na 2 SO 4 and the solvent evaporated. Chromatography of the residue on an SPE column of silica gel (eluting cyclohexane gradient / ethyl acetate 8/2 to 2/8) gives 3α-hydroxytagitinyl C cyclohexanecarboxylate (12 mg, 97%) 3α-hydroxy-tagitinyl C cyclohexanecarboxylate 1H NMR: 3q T f J d 122 m - 125 s - 123 m -. ! $! m - 1. 42 153 454 m -. s - 210 d i6.5.6 2.33 t 10.9 $ 6 9.3., It 2t 4. y s - 4 d! &% 34! E! \ Yes! 5.19 4! C4 5:! 5 3 513 4çÆ9a A 3.1 ç 24

94 13 C NMR: 176.4; 170.5; 149.1; 139.3; 137.0; 132.5; 122.2; 122.0; 75.1; 73.6; 70.9; 69.1; 51.4; 43.9; 43.6; 29.7; 29.6; 29.0; 26.5; 26.1; 26.0; 20.7. e2- Deprotection of the C3 alcohol and then deprotection of the C11-C13 double bond:

Step 1: Tetrabutylammonium fluoride (TBAF, 261 μL, 261pmol, 7eq) is added to a solution of

tertbutyldimethylsilyloxy-13-morpholino-tagitinyl C

cyclohexanecarboxylate (22 mg, 37 pmol) in anhydrous tetrahydrofuran (THF) (0.5 mL). The reaction is stirred for 30 minutes. The solvent is evaporated and the residue taken up in ethyl acetate and then washed with water (3x15 mL) and with brine (1x15 mL). The aqueous phase is extracted with ethyl acetate

(2x30 mL) and the combined organic phases are dried over anhydrous Na 2 SO 4 and the solvent evaporated. Chromatography of the residue on an SPE column of silica gel (isocratic ethyl acetate eluent) gives 3α-hydroxy-13-morpholinotagitinyl C cyclohexanecarboxylate (17 mg, 95%).

3α-hydroxy-13-morpholino-tagitinyl C cyclohexanecarboxylate 1H NMR: 31. :,. pm Type I ',. - 1 64 .. 15..6 1.87 - 2.> 8 del D: 15.? 6.D 2.2; t 1 .G. 3.4 2 .. .5 * cI 10.5.2. 2.118 4.0 2.f ~ m 3.5O • t 4. 5: Dl z7 - 5 .., C 1'O. 1 5 .55 vt `.`_ 5.75 d t u..h: '1. *.

NMR: 178.6; 176.8; 148.8; 139.2; 132.7; 122.5; 74.8; 73.5; 70.9; 69.4; 67.6 (2C); 57.3; 55.2 (2C); 48.8; 43.9; 43.6; 41.8; 30.0; 29.5; 28.9; 26.5; 26.2; 26.0; 20.6.

Step 2: The 3α-hydroxy-13-morpholino-tagitinyl C cyclohexanecarboxylate (17 mg, 36 pmol) is diluted in an excess of methyl iodide (1 mL, 16 mmol, 445 eq). After stirring for 20 h at RT, a white precipitate of 3α-hydroxy-13-methylmorpholinium-tagitinyl C cyclohexanecarboxylate is observed. The excess of methyl iodide is evaporated under a stream of nitrogen and the residue is taken up in ethyl acetate and then treated with a saturated solution of NaHCO3 (2 × 20 mL). The aqueous phase is extracted with ethyl acetate (2 × 20 mL). The organic phases are dried over anhydrous Na 2 SO 4 and the solvent evaporated. Chromatography of the residue on an SPE column of silica gel (gradient cyclohexane / ethyl acetate 6/4 to 0/10 eluent) leads to 3α-hydroxy-tagitinyl C cyclohexanecarboxylate (12 mg, 82%). Oxidation of the C3 alcohol to the ketone Dess-Martin periodinane (75 μL, 22 pmol) is added to a solution of 3α-hydroxy-tagitinyl C cyclohexanecarboxylate (9 mg, 22 μmol) in dry dichloromethane (500 ml). pL). A white precipitate appears. During the reaction, 500 μl of a solution of 10 μl of water in 10 ml of anhydrous dichloromethane are added. After stirring for 5 h at RT, the reaction medium is diluted with anhydrous ether (1 mL) and the solvent is evaporated. The residue is taken up in anhydrous diethyl ether and washed with a 1: 1 mixture of Na 2 S 2 O 3 (10% = 10 g in 100 ml of water) and saturated NaHCO 3 (1 × 30 ml), then with water (1 × 30 ml) and water. brine (1x30 mL). The aqueous phases are extracted with ether (2 × 30 ml) and the combined organic phases are dried over Na 2 SO 4 and the solvent evaporated. Chromatography of the residue on an SPE column of silica gel (cyclohexane / isocratic 6/4 ethyl acetate eluent) leads to tagitin C cyclohexanecarboxylate (7.2 mg, 82%). 1.14.2 Cases of simultaneous protections and deprotections of the C11-C13 double bond and of the C3 alcohol Synthesis scheme: OH OH TBDMSC1, Imidazole TBDMSOII1. DMF, 2h, t.a. O 3? -Hydroxy-TC HOII '• HO III, RCOC1, Pyridine CH2Cl2, ta. 24h-72h TBDMSOIII • In this case, the C3 alcohol and the C11-C13 double bond are protected simultaneously during the same step and are also deprotected in a single step. The other steps of the synthesis of the ester derivatives are then similar to those described previously for the method with successive protections and deprotections. Thus, the action of TBDMS chloride in the presence of excess imidazole leads to 3a-TBDMSO-11a-13-imidazolo-tagitinin C and 3a-TBDMSO-1113-13-imidazolo-tagitinin C and then the hydrolysis by the Sodium methoxide provides the corresponding protected C-tagitinols. After esterification of the C-8 alcohols with the appropriate acylating agent (RCOC1) and double deprotection with nBu4NF, the oxidation of barium manganate or Dess-Martin periodinane of the C-3 hydroxyl leads to the esters. of desired C tagitinyl. These reactions follow the previous experimental protocols, of which they differ only in reaction times. 1.14.3 Direct esterification of tagitinol C

Tagitinol C, obtained in particular enzymatically, was also esterified directly according to the protocol described above (1.14.1 d).

The products obtained by these methods (1.14.1, 1.14.2 and 1.14.3) are described below.

Tagitinyl C 4-phenylbenzoate H NMR: .i Type el (F a 1 ... 47 1 ... 2 .2..22 dd 1: 4.0, t <.. l 2..54 dd 14.0, 5_1 3.59 3..72 .dq 3.1; 1.6 5..53 & A. 2 $ 643! 5..7G 9.2 5.93 1.a 5.97 9,2,1.5 1.5 5.31 d! Tl 5. 17.1 7A2 m 7.3 24 t 7.3 7.59 d 7, G 7.73 8 ... 5, 7.95 d s ... 5 13 C NMR: 198.2, 170.9, 165.8, 139.7, 138.1, 137.9, 130.9 (2C) 129.5, 129.4, 128.3 (2C); 128.2 7

7; 7; 4

8; 4

0; 2

1; ## STR1 ## 146.8; 140.5; 130.8; 130.1 (2C) (2C); 124.9; 77.3 Tagitinyl C adamantane carboxylate C. .., -., - Te,, H3 1H NMR: 2, 3tet.l (ppm 1.43 ..58 1.85 I.8g 2.81 2.31 .3.57 5.w 5.8-1 5.91 6.2) 6.25 5:90 Type J (Hz) s _ m. d 27 d dd dd 14.0, 6: 1 dq 3.2.1..8 ddd .2 ,. 34 of D.:.8 d .c1q 9.2.,. 1.5 d 1.5 d 15: 8 d 424 13 C 3g2: 198.1, 170.6; 161.9; 139.4; 138.6; 130.7; 124.5; 77.1; 75.0; 48.8; 47.8; 39.3 (6C); 37.1 (5C); 29.1; 28.9 (3C); 19.8 Tagitinyl C benzoate oH 0 1H NMR: 5 t el Type .1.46 s. 1 ... 2 2..20 14.0, 9.8 2..5.1 14 $ 5.6 370 3. 1, .1..5 555 d & 9.8., & A ,. It 5.58 dg.2 5.88 d 1 ... 5 5.g5 4-1q 9.2, 1.5 6.18 1.5 5.30 d 17..4 8. ', 1)> S 1.71 7.48 t 7.8 7_.61 7.5 7.88 d & S 13 NMR: 198.2; 170.8; 165.9; 161.7; 139.7; 138.1; 137.9; 134.5; 130.8; 130.5; 130.3 (2C); 129.7 (2C); 124.9; 77.2; 76.7; 72.5; 48.7; 48.0; 29.1; 19.8 Tagitinyl C cyclohexane carboxylate -. - ..... 0_ .... - \ _ ---- 0 HaC 1H NMR: 995 Honey m Type z) 1_28 m 1 .43 1.58 m 1 to 65 m _ .1.72 m - 1.88 d 1.3 2118 14.0 , 9: 9 2.31 1 0, 6.1 3.49 s 8.57 8.2, 1..9 5 to 36 ddd 9.7 6 to 3.3 5.4.8 9.1 5.81 1..6 501 dq! D.3, 629 1.6 9.26 d 17.9 8.89 d 17..8 13 C NMR: 198.2; 175.3; 170.9; 161.6; 139.5; 138.1; 138.0; 130.6; 124.6; 77.0; 75.1; 72.4; 48.8; 47.8; 43.9; 29.7; 29.5; 29.0; 26.5; 26.1; 26.0; 19.8 Tagitinyl C cyclohexylacetate NMR: I005 Ml.gt.l (ppm Type zl O, 8D m 1.12 m, 27 1.43 s 1.85 m .6 '., A to 7' '<A> ä88 d 1.2 2: 0.2 d 37 2 d 14..0., 101 2:34 dd 14G .. 5..l 3.55 3.2, .7 5.31 ddd 51., 31 46 r 9.2 552 d 1.8 5.91 D.2 to 15 d 1 .. 8.25 d 1T4 17.1 13 C NMR: 198.2, 172.5, 170.7, 161.5, 138.1, 138.0, 130.6, 124.5, 77.0, 75.4, 72.4, 48.8, 47.8, 42.7, 35.5, 33.6, 33.5, 29.0, 26.9, 26.8, 26.7. 19.8 Tagitinyl C cyclopentane carboxylate 101 ## STR1 ##. ## EQU1 ## 8 5:30 ddd 9..9 ,, 6_3, 14 5.4.8 d 9.2 5.82 1 ... 8 & m q 9 .2,. 6.21 1..8 5.25 d .1 3.89 t7. 13 C NMR: 198.2; 176.0; 170.9; 161.6; 139.5; 138.1; 138.0; 130.6; 124.5; 77.0; 75.2; 72.4; 48.8; 47.8; 44.6; 30.8; 30.2; 29.0; 26.5; 26.3; 19.8 Tagitinyl C cyclopentylpropyloate OH 0 8C * L7. 4 :: = 3M 5 102 H 1 H NMR: δ (ppm Tee 1.04 m -1.43 1 ... 49 m 1..58 m -1. 59 m 1..88 d 05 2 ... 04 cf.:1 142, 9 '2..59 s 217 m 2.33 dd 5.8 3 ... 49 s 3..55 dq 34 1 .7 5.31: ddd T5 .2. 3.4 5 ... 47 d 9 ... 2 5.81 d 1..8 5.91 9.2., 1.5 5..25 d 1.5 6.26 d 47! 5.88 d 13 C NMR: 198.1; 173.3; 170.8; 161.4; 139.5; 138.1; 138.0; 130.6; 124.5; 77.0; 75.3; 72.4; 48.8; 47.9; 40.4; 34.1; 33.0 (2C); 31.7; 29.0; 25.8 (2C); 19.8 Tagitinyl C cyclopropanecarboxylate 103 H3d 1H NMR: 5 TiglO.ppm Tvpe J; z 0: 1 41 m - 1..43 s! 3a 1.2 2.04 del 4 2.2.8 2..33 d4 14 1 3.45-) 3 .55 .dq 1..8 5..28: Md 6. 3, 3.2 5..48 dc2 .. 82 1.8 5:91 2215 6 22 1..5 b..26 17. 1 6.88 .1 Tl 132 NMR: 198.2; 174.1; 170.9; 161.5; 139.6; 138.0; 137.9; 130.7; 124.6; 77.1; 75.5; 72.4; 48.7; 47.8; 29.0; 19.8; 13.5; 8.7; 8.5

Tagitinyl C pent-4-enyloate 104 0. . . . ---- 1H NMR:, elp 3t p, 1..43 s 1.88 d 1 ... 5 2.05 14 101 2.23 m 222 3.:g, 154 3.4.,. 4:95 427. 1..5 5.05 5..32 .ddd 262; & 4 8.9 5.75 m 17.1. 1851 5.82 d 1 ... 5 92 .5 5..21 1..5. 8.25 .1 6.83 17.4 13 C NMR: 198.2; 172.5; 170.8; 161.4; 139.5; 138.1; 137.9; 137.8; 130.6; 124.6; 116.0; 77.0; 75.6; 72.4; 48.8; 47.8; 34.0; 29.4; 29.0; 19.8 Tagitinyl C p-fluorobenzoate OH 0.F.a., 1H NMR: 105 5 ee.l. (Ppm.) 1.45 1.91 _ 251 X1: 1 6..4 7__ Il., 1. q 5.53 ddd .g, _7 6.5 3. 1 5.67 5.9 5.83 1.8 5.9 9.2, 1..5 6.13 1.8 6.3 17.1 5.95 d .17,1 71 9 t 9.'O 7.92 dd 9.0, 5.3 13 NMR: 198.1, 170.9, 166.9, 165.0, 161.7, 139.7, 138.0, 137.8, 133.1 (2C), 130.8, 127.0, 125.0, 116.8 (2C), 77.2, 76.9, 72.5, 48.7, 47.9, 29.1, 19.8, Tagitinyl, p-methoxybenzoate 106 If 0 1H NMR: 1el little (TP.:'= ', 1.45 s 1.91 1..5 217 rld 14_3, 1 Cl 2..49, 1;: 1 14..G, 6.1 134, s 363 3.2.1 .7 3..83 s 5_51 5..52 2: 5. & 8 d 1.8: 5_96 dq 9.21.5 516 d .1.5 6.2 6..95 d 17..1 5.96 .d 7.32 S .. 9, 2941697 107: 196.3, 170.9, 165.6, 164.9, 161.8, 139.6, 138.1, 132.4 (2C), 130.7, 124.8, 122.7, 115.0 (2C), 77.3, 76.3, 13 C NMR 138.0;

72.5; 56.4; 48.8; 48.0; 29.1; 19.8 ùCH3 T g tinyl C senecioate OH y H 15 ° H NMR: q + ~:, Jz d 1.43 s - 18 12 t d! 2 14.3 m4 s-! 2 2.34 1! ] &% ÆO 5 3 - 35 m - 5. d ç $ t! &! 12 m - 58 d) 3 5_91: 21.5! 3 d) $ C '4 17 & 8 lE5 NMR: 199.0; 161.4; 160.1; 138.1; 130.6; 124.4; 115.6; 77.1; 74.6; 49.0; 48.0; 28.927.4 ;; 20.4; 19.8

1.14.4 Isoprene-type side chain ester derivatives obtained from heliangolide-type precursors, provided that these particular isoprenic-type derivatives (i.e. with a saturated or unsaturated 4-carbon side chain) can be prepared by the method 8 described above, they can be prepared also from heliangolide derivatives such as heliangin, leptocarpine, eroforine, senecioate, 2-methylbutanoate or E-tagitinyl 3-methylbutanoate, and tagitinin E extracts from Helianthus tuberosus. A protocol for preparing the compounds is exemplified below.

Tagitinyl C tiglate OH Heliangin, heliangolide isolated from Helianthus tuberosus (Morimoto et al., Tetrahedron 1966, 22, 3173-3179), is treated as follows: Dess-Martin periodinan (DMP) (1 mL, 0.33 mmol) is added to a solution of heliangin (54 mg, 0.15 mmol) in dry dichloromethane (3 mL). After addition of 1.5 ml of dichloromethane saturated with water, the reaction medium is stirred for 5 hours at RT. The mixture is diluted with ether and washed with 10% Na 2 S 2 O 3 solution and NaHCO 3 (1: 1) and then with water and brine. The washing solutions are re-extracted with ether and the combined organic phases are washed with brine, dried with anhydrous Na 2 SO 4 and concentrated. Chromatography of the residue on silica SPE column (cyclohexane / ethyl acetate gradient: 7/3 to 5/5) gives a white powder (49 mg, 92%). 1H NMR: δ 510 Elel: 1.ppra Type J I! iron! s 1 .70 cein 1.2 1 ... 71 dq .7, D, 1..2 1..r'O 1.2 2.50 s .14.0.a 9S 23 (Id 6.1 3 ... 5.2 3.50 al & Æ .1. 3, 5..3.3, 6.3, 3.1: 5.54 9-2 d 1.8 5..92 1..5 618 5.26 171 0.70 qtl J14 5.g.1 171 13 C NMR: 198.2; 170.9, 167.3, 161.7, 139.6, 139.2;

138.1 (2C); 130.6; 129.0; 124.5; 77.2; 75.9; 72.4; 48.8; 48.0; 29.0; 19.8; 14.6; 12.1. The following compounds have also been prepared according to this process. Tagitinyl C 2 -methylbutanoate O :( -,:::, NMR: 109 110, ee 0.73 t 7. 1 .00 7.0 .34 m - 1.44 .1.56 - 1.88 1.2 2.04 .dd 13.0, 9.9 2.2.1 2.34 dd 13.7, 6.1 3.58 _.4,1.8 ddd 6.2a 3.4 5.48 8.2 5.91 .dq 9..2.1 ..5 6.21 1 7A. 6.9 17.1 Tagitinyl C 3-methylbutanoate OH 0 H -) C .., - ./CH - :. - f '- reads -: C 0.. ,).! H NMR: titi ppin Typ-f! iK) 0.85 d 5 T. 0..85 1.43 1.88 .12: 2.02 t 2.04, dd 110, 9..9 2.34, dd 14..0, .156: d 3.3., 1. 5..32 ddd 6..2.,. 3 .4 5.4.7 dg..2 5. d 1..8, 5..91 9.1, 1.4 6.21 d 1..3 6 ... 2.6 d 17..1 8.88 d 17.1

111 13 C NMR: 198.2; 172.5; 170.8; 161.5; 139.5; 138.1; 138.0; 130.6; 124.5; 77.0; 75.4; 72.4; 48.8 (2C); 47.8; 29.0; 26.4; 22.5 (2C); 19.8 Tagitinyl C methylacrylate OH 1H NMR: el Typa Dl pm 1.44. s 1.72 hr_ 1.87 .1 .89 2 2.0D! a 7.1C4 2a.4.1 dd 14..0a 6.4 3..52 s 33.. 3.2.,. 4 3 5 ... 40 ddd 6.3., 3..2 5.52 d 9..2 5.84. 1_5 5..91 dq .5 aee qq 7.2 ,. 1.5 6.21 d 1 .8 D..26 .d IT4 6.92 I7.1 13 C 3M2: 199.2; 170.9; 167.2; 161.7; 139.6; 139.5; 138.1; 138.0; 130.7; 128.3; 124.6; 29.1; 77.1; 75.4; 72.4; 48.9; 47.9; 20.5; 19.8; 15.9. Tagitinyl C angellate OH o 15 H NMR: 5 pin Type J X1..44 ..4 '- 1. + T: 1..8.`_ tc 1 ..2 2:07: m - 2.41: d 1 1., .1 3.52 s -?., .. 62 r1q 3.2a.1.8 534 dirtr, .. i. ; 3.32 5.55 1_ti S.57 quv 5 '_'4 .1 33 + _4 5.92: m `... 2r .1? .1: 6.92; 11.13 C NMR: 198.1; 170.8; 166.7; 161.6; 139.6; 138.1; 138.0;

137.1; 130.7; 126.7; 124.7; 77.2; 76.3; 72.4; 48.6; 47.9; 29.1; 19.8; 18.3. 1.15. Preparation of ether derivatives

1.15.1. Successive protections / deprotection Synthesis scheme: 112 TBDMSO, `, 8TBDMSO OH a. McI / NaHCO3 b. The preparation of the C-tagitinyl ethers was carried out according to the preceding ester synthesis process involving successive protections and deprotections. We converted 3-hydroxy-C tagitinins to the corresponding silyl ethers by the action of tert-butyl-dimethylsilyl triflate (TBDMSOTf) in the presence of 2,6-lutidine. After protection of the 11,13-double bond by addition of morpholine and chemical hydrolysis of the C-8 ester, the etherification of the 3- or 3-TBDMSO-11α-13-morpholino-tagitinol C with an RC1 chloride such that p-methoxybenzyl chloride (PMBC1) in the presence of silver triflate and 2,6-di-tert-butylpyridine leads to the corresponding ethers. After deprotection and oxidation with tetrapropylammonium peruthenate (TPAP), the desired ether is obtained. a-Protection of the alcohol with C-3 To a solution of 3α-hydroxy-tagitinin C (234 mg, 0.75 mmol) in dichloromethane (8.5 ml), 2,6-lutidine (185 μl, 1.59 mmol) and TBDMSOTf (208 μL, 0.91 mmol) under a nitrogen atmosphere. The reaction mixture is stirred for 2 h at RT then added with water (5 mL) and diluted with ethyl acetate (25 mL). The organic phase is washed with water (1x15 ml), then with brine (1x15 ml) and the aqueous phases are extracted with ethyl acetate (3x20 ml). The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue is purified by medium pressure chromatography (gradient: cyclohexane / ethyl acetate 9/1 to 7/3 in 1 hour) to give 3a-TBDMSO-tagitinin C (228 mg, 65%). b- Protection of the double bond in 11,13 The protocol is similar to that described for ester derivatives. c-Hydrolysis of the C-8 Ester The protocol is similar to that described for the ester derivatives.

d-Etherification of the alcohol at C-8 and / or the alcohol at C-10 Example with the PMBC1 A solution of 3a-TBDMSO-11a-13-morpholino-tagitinol C (32 mg, 0.066 mmol) in anhydrous CH 2 Cl 2 (1 mL) are added silver triflate (51 mg, 0.198 mmol), di-tert-butylpyridine (52 μL, 0.23 mmol) and p-methoxybenzyl chloride (29 μL). 0.21 mmol). After stirring for 6 h at RT, an aqueous solution of 10% potassium carbonate (2 ml) is added, filtered through Celite and washed with ethyl acetate. Evaporation of the filtrate, and chromatography on silica SPE column (gradient: cyclohexane / ethyl acetate 9/1 to 4/6) leads to the following products (24.5 mg, 45%).

3α-tert-butyldimethylsilyloxy-8,10-di-p-methoxybenzyloxy-11α-13-morpholino-tagitinyl C: OMe-O 1H NMR: 7.29 (d, J 8.6, 2H); 7.03 (d, J 8.5, 2H); 6.88 (d, J 8.7, 2H); 6.73 (d, J 8.6, 2H); 5.58 (dd, J 15.8, 9.4, 1H); 5.45 (d, J, 15.8, 1H); 5.11 (d, J 9.2, 1H); 5.05 (d, J 10.1, 1H); 4.95 (t, J 9.9, 1H); 4.47 (d, J, 10.9, 1H); 4.39 (d, J

10.9, 1H); 4.37 (s, 2H); 3.82 (dd, J 4.9, 4.9, 1H); 3.76 (s, 3H); 3.73 (s, 3H); 3.51 (m, 4H); 2.64 (m, 2H); 2.34 (m, 2H); 2.03 (d, J 5.1, 1H); 1.80 (m, 4H); 1.41 (s, 3H); 0.91 (s, 9H); 0.11 (s, 3H); 0.09 (s, 3H). 13 C NMR: 136.16; 134.16; 130.34 (2C); 129.94 (2C); 132.13;

114.68 (2C); 114.38 (2C); 75.43; 74.93; 72.51; 70.95; 67.58 (2C); 65.27; 57.19 (2C); 55.9 (2C); 43.48; 26.22 (3C); 24.20;

21.34; -3.66; -4.70.25 3α-tert-butyldimethylsilyloxy-10-p-methoxybenzyloxy-1α-13-morpholino-taginol C: OMe 1H NMR: 7.32 (d, J 8.7, 2H); 6.91 (d, J 8.5, 2H); 6.63 (s,

1H); 5.63 (dd, J 15.7, 9.5, 1H); 5.42 (d, J 15.7, 1H); 5.12 (m, 2H); 4.98 (t, J, 10.3, 1H); 4.56 (d, J 10.4, 1H); 4.37 (d, J 10.5, 1H); 3.78 (m, 4H); 3.63 (m, 4H); 2.91 (dt, J 11.9, 9.1, 1H); 2.75 (dd, J 12.8, 2.8, 1H); 2.61 (m, 2H); 2.42 (t, J 12.5, 1H); 2.33 (m, 2H); 1.94 (m, 1H); 1.83 (m, 4H); 1.36 (s, 3H); 0.89 (s, 9H); 0.09 (s, 3H); 0.05 (s, 1H). 13 C NMR: 177.04; 148.96; 136.89; 133.64; 130.17; 122.57; 114.67 (2C); 76.03; 74.88; 67.14 (2C); 64.81; 62.96; 60.21; 55.92; 45.20; 40.11; 26.24 (3C); 24.14; 21.14; -3.76; -4.73.

N.B .: It is then possible to esterify the unreacted C-8 free alcohol as in the example below: Cyclohexanecarboxyl chloride (68 μL, 0.5 mmol) and

pyridine (327 μL, 4 mmol) are added to the 3α-tert-butyldimethylsilyloxy-10-p-methoxybenzyloxy-11α-13-morpholino-

Tagitininol C (9.5 mg, 0.016 mmol) in anhydrous CH2Cl2 (2.8 mL). After stirring for 4 h at RT, the reaction mixture is flooded with water (2 mL) and then filtered through Celite, which is then rinsed with ethyl acetate. Evaporation of the filtrate under vacuum and chromatography on silica SPE column of the residue

(gradient: CH 2 Cl 2 / methanol 10/0 to 97/3) gives the desired ester (9.7 mg, 86%). 6α-tert-butyldimethylsilyloxy-10-p-methoxybenzyloxy-11α-13-morpholino-1-pentyl-C-cyclohexanecarboxylate: 1H NMR: 7.19 (d, J 8.5, 2H); 6.86 (d, J 8. 7, 2H); 5.64 (dd, J 15.8, 9.7, 1H); 5.47 (d, J 15.8, 1H); 5.29 (m, 1H); 5.15 (m, 2H); 4.95 (t, J 10.1, 1H); 4.38 (d, J 11.2, 1H); 4.32 (d, J 11.7, 1H); 3.77 (s, 3H); 3.54 (m, 2H); 2.71 (m, 1H); 2.62 (m, 2H); 2.33 (m, 2H); 1.86 (s, 3H); 1.8-1.6 (m, 5H); 1.4-1.2 (m, 8H); 0.88 (s, 9H); 0.10 (s, 3H); 0.05 (s, 3H). 3α-tert-butyldimethylsilyloxy-8-p-methoxybenzyloxy-11α-13-morpholino-tagitinyl C: OH OMe 1H NMR: Merl '.p.rem, Typa 0s - 0_.08. s - 1.32 s - t d 15.1 1 82 s - i: 1 t 5.0 23 2.61 m - 2 70 d! t7: 2.87 s - 3.51 m - 3 d æo 37 s - 4.40 to 11 to 4 11.3 & 93! T9 5.04 at S & D 154 5.57 to 8.87 d æ 7.24 8 ... 5 13 C NMR: 179.4; 160.1; 148.3; 139.1; 132.6; 132.2; 130.6 (2C); 123.0; 114.4 (2C); 75.3; 75.0; 72.8; 70.9; 70.7; 67.7 (2C); 57.0; 55.9; 55.3 (2C); 48.7; 43.9; 42.5;

29.1; 26.2 (3C); 21.2; 18.9; -3.8; -4.7. e-Deprotection of the double bond at 11,13 A solution of the derivatives obtained in the preceding step (24.6 mg, 0.35 mmol) in iodomethane (1 mL) is stirred for 20 hours at RT.

After evaporation of the iodomethane, the residue diluted in ethyl acetate (1 ml) is added an aqueous solution of potassium carbonate at 10% (2 m). After stirring for 2 h, filtering on celite, rinsing with ethyl acetate and concentration of the filtrate, chromatography on the silica SPE column of the residue (elute: cyclohexane / ethyl acetate 8/2) gives the following products: (17 mg, 69%). 3α-tert-butyldimethylsilyloxy-8,1-di-methoxybenzyloxytaginyl C: 117,118 OMe 1H NMR: 7.31 (d, J 8. 6, 2H); 7.03 (d, J 8. 6, 2H); 6.91 (d, J 8.7, 2H); 6.77 (d, J 8.7, 2H); 6.09 (d, J 3.4, 1H); 5.83 (d, J 3.1, 1H); 5.57 (dd, J 15.9, 9.5, 1H); 5.46 (d, J 15.9, 1H); 5.12 (m, 2H); 5.04 (t, J 9. 8, 1H); 4.46 (d, J 10.8, 1H); 4.36 (d, J 11.0, 2H); 4.33 (d, J 11.2, 1H); 3.84 (m, 1H); 3.77 (s, 3H); 3.74 (s, 3H); 3.09 (m, 1H); 2.00 (m, 1H); 1.81 (m, 4H); 1.37 (s, 3H); 0.91 (s, 9H); 0.11 (s, 3H); 0.08 (s, 3H). 3α-tert-butyldimethylsilyloxy-10-p-methoxybenzyloxy-tagitinyl C cyclohexanecarboxylate: 1H NMR: 7.20 (d, J 8.6, 2H); 6.87 (d, J 8.7, 2H); 6.13 (d, J 3.4, 1H); 5.79 (d, J 2.9, 1H); 5.62 (dd, J 15.8, 9.5, 1H); 5.50 (d, J 15.8, 1H); 5.33 (m, 1H); 5.23 (m, 1H); 5.14 (m, 1H); 5.06 (t, J 9. 7, 1H); 4.39 (d, J 11.2, 2H); 4.32 (d, J 11.0, 1H); 3.77 (s, 3H); 3.08 (m, 1H); 1.99 (dd, J 15.8, 5.4, 1H); 1.87 (m, 4H); 1.74 (m, 2H); 1.64 (m, 2H); 1.58 (m, 1H); 1.37 (s, 3H); 1.3-1.2 (m, 5H); 0.88 (s, 9H); 0.10 (s, 3H); 0.05 (s, 3H).

Deprotection of the C-3 Alcohol TBAF (233 μL, 0.23 mmol) was added to a solution of the foregoing compounds (17 mg, 0.033 mmol) in dry THF (400 μL). After stirring for 1.5 h at RT, the reaction medium is embedded with water (2 mL), filtered through Celite, which is then washed with ethyl acetate. Concentration of the filtrate and chromatography on silica SPE column of the residue (gradient: cyclohexane / ethyl acetate 7/3 to 6/4) lead to the following compounds (11 mg, 80%).

3α-hydroxy-8,10-di-p-methoxybenzyloxy-tagitinyl C: OMe 1H NMR: 7.33 (d, J 8.6, 2H); 7.05 (d, J 8.6, 2H); 6.92 (d, J 6.78 (d, J 8. 6, 2H) 6.09 (d, J 2. 6) 5.73 (d, J 5.60 (dd, J 15.8, 9.6, 1H) 5.46 (d, J 15.8 , 1H); J 10.3, 1H); 5.05 (d, J 9.8, 1H); 4.97 (d, J 9.2, (d, J 10.9, 1H); 4.42 (d, J 10.7, 1H); 4.38 (d, J 11.4, 1H), 4.34 (d, J 11.2, 1H), 3.87 (m, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.23 (s, 1H), 3.10 (m, 1H); 2.00 (m, 1H), 1.83 (m, 4H), 1.38 (s, 3H).

3α-hydroxy-10-p-methoxybenzyloxy-tagitinyl C cyclohexanecarboxylate: 1H NMR: 7.21 (d, J 8.6, 2H); 6.87 (d, J 8.7, 2H); 6.12 (d, J 3.3, 1H); 5.79 (d, J 2.9, 1H); 5.66 (dd, J 15.8, 9.9, 1H); 5.49 (d, J 15.8, 1H); 5.35 (m, 1H); 5.22 (m, 1H); 5.06 (t, J 9.7, 1H); 4.99 (m, 1H); 4.41 (d, J 11.1, 1H); 4.31 (d, J 11.5, 25H); 3.77 (s, 3H); 3.24 (d, J 5.1, 1H); 3.09 (m, 2H); 2.01 8.7, 2H); 2.3, 1H); 5.13 (d, 1H); 4.46 0 (dd, J 15.8, 5.3, 1H); 1.87 (s, 3H); 1.74 (m, 2H); 1.64 (m, 2H); 1.58 (m, 1H); 1.37 (s, 3H); 1.35-1.2 (m, 5H).

Oxidation of the alcohol at C-3 TPAP (0.8 mg, 2.3 pmol), N-methyl-morpholine-N-oxide (NMO) (4 mg, 34 pmol), molecular sieves 4 (10 mg) and anhydrous methylene chloride (90 μL) are added to the mixture of step f (11 mg, 22 pmol). After stirring for 2 h at RT and concentration, the chromatography of the residue on a silica SPE column (gradient: cyclohexane / ethyl acetate 8/2 to 7/3) gives a mixture of C-tagitinyl ethers (8 mg). , 70%) which is separated by HPLC (eluent: (cyclohexane: THF 95: 5) / ethyl acetate 9/1), thereby giving access to the following compounds: 8,10-di-p-methoxybenzyloxy-tagitinyl C (4.3 mg): 1H NMR: 7.27 (dt, J 8. 8, 2.7, 2H); 7.11 (dt, J 8.8, 2.7, 2H); 6.95 (d, J 17.0, 1H); 6.91 (dt, J 8.7, 2.8, 2H); 6.83 (dt, J

8.7, 2.8, 2H); 6.32 (d, J 17.0, 1H); 6.14 (d, J 2.0, 1H); 5.88 (dd, J 9.5, 1.5, 1H); 5.61 (d, J 1.5, 1H); 5.39 (dd, J 9.0, 1.5, 1H); 4.44 (d, J 11.0, 1H); 4.43 (d, J 11.0, 1H); 4.34 (d, J 11.0, 1H); 4.18 (d, J 11.0, 1H); 3.86 (ddd, 8.5, 5.0, 3.0, 1H); 3.78 (s, 3H); 3.75 (s, 3H); 3.39 (m, 1H); 2.60 (dd, J

14.5, 5.5, 1H); 2.11 (dd, J 14.5, 9.0, 1H); 1.87 (d, J 1.5, 3H); 1.55 (s, 3H). 13 C NMR: 198.05; 171.19; 160.40; 160.21; 160.04; 139.74; 139.28; 138.06; 132.17; 132.11; 131.03; 130.62 (2C); 130.04

(2C); 122.92; 114.71 (2C); 114.56 (2C); 80.55; 77.98; 77.09; 72.88; 65.87; 55.96; 55.92; 49.50; 47.46; 23.77; 19.87. 1H NMR: 7.12 (d, J 8.6, 2H); 6.84 (d, J 8.6, 2H); 6.83 (d, J 11.6, 1H); 6.22 (d, J 11.6, 1H); 6.16 (d, J 1.8, 1H); 5.90 (dd, J 9.3, 1.4, 1H); 5.73 (d, J 1.8, 1H); 5.40 (d, J 9.3, 1H); 4.44 (d, J 10.9, 1H); 4.18 (d, J 10.9, 1H); 3.91 (ddd, J 9.0, 5.5, 2.9, 1H); 3.76 (s, 3H); 3.40 (m, 1H); 3.29 (s, 1H); 2.45 (dd, J 14.1, 5.5, 1H); 2.09 (dd, J 14.1, 9.0, 1H); 1.86 (d, J 1.4, 3H); 1.45 (s, 3H). NMR: 198.35; 161.42; 160.36; 139.86; 139.4; 138.54; 131.18; 130.56 (2C); 130.44; 122.87; 114.54 (2C); 81.24; 77.18; 73.03; 72.27; 55.92; 49.37; 48.96; 28.96; 19.74.

10-p-methoxybenzyloxy-tagitinyl C cyclohexanecarboxylate (0.8 mg): 1H NMR: 7.32 (dt, J 8. 6, 2.9, 2H); 7.03 (d, J 16.9, 1H); 6.93 (dt, J 8.6, 2.9, 2H); 6.35 (d, J 17.0, 1H); 6.18 (d, J 2. 0, 1H); 5.89 (dd, J 9.2, 1.6, 1H); 5.68 (d, J 1. 7, 1H); 5.49 (d, J, 9.1, 1H); 5.24 (ddd, J 9.5, 5.8, 3.3, 1H); 4.48 (d, J 10.9, 1H); 4.39 (d, J 10.9, 1H); 3.78 (s, 3H); 3.55 (m, 1H); 2.49 (dd, J 14.3, 5.9, 1H); 2.08 (m, 1H); 2.05 (dd, J 14.2, 9.9, 1H); 1.88 (d, J 1.4, 3H); 1.72 (m, 2H); 1.64 (m, 2H); 1.57 (m, 1H); 1.53 (s, 3H); 1.23 (m, 5H). 8-p-methoxybenzyloxy-tagitinyl C (1.5-2 mg). The following derivative was isolated during purification by HPLC and results from a side reaction due to the presence of formaldehyde in the alkylating agent. 10-p-methoxybenzyloxy-8- (p-methoxybenzyloxy) -methoxy-tagitinyl C (0.5 mg): 1H NMR: 7.28 (d, J 8.7, 2H); 7.20 (d, J 8.7, 2H); 6.98 (d, J 16.6, 1H); 6.90 (dd, J 8.7, 2.0, 2H); 6.88 (dd, J 8.7, 2.0,

2H); 6.32 (d, J 17.0, 1H); 6.19 (d, J 1.7, 1H); 5.90 (dd, J 9.3, 1.5, 1H); 5.70 (d, J 1.7, 1H); 5.41 (d, J.9.7, 1H); 4.64 (d, J 7.1, 1H); 4.49 (d, J 7.1, 1H); 4.44 (d, J 11.1, 1H); 4.36 (s, 2H); 4.35 (d, J 11.1, 1H); 4.08 (m, 1H); 3.77 (s, 3H); 3.76 (s, 3H); 3.44 (s, 1H); 2.55 (dd, J 14.6, 5.4, 1H);

2.11 (m, 1H); 1.87 (d, J 1.4, 3H); 1.52 (s, 3H). 13 C NMR: 198; 172; 160; 137.7; 132; 130.58 (2C); 130.02 (2C); 123.45; 114.72 (2C); 114.71 (2C); 94.66; 78.9; 77.13; 70.17; 65.98; 55.95; 55.93; 49.34; 48.50; 23.86; 19.89.

The following ethers result from the etherification with benzyloxy-methyl chloride: 8,10-benzyloxy-methoxy-tagitinyl C: 1H NMR: as: Pt Type 1.51 s 2.13 m 252 14.6, 5.2 4- 17 ddfi 8.7, $ .1 4.46 s 4.55 d,. .4,62 d 11 4..67 d 105 70 4.82 d 7.6 4.67 d 7.6 5.4.1 9.5. 1.5 5.76 5.89 z%! 2 6.17 d 1.55 168 7.05 d 17.1 7.32 m 13 C NMR: 198.0; 171.2; 159.8; 139.4; 139.3; 139.1 137.8; 131.7; 129.6-128.4 (aromatic 10C); 123.7; 95.0 91.6; 79.0; 78.5; 77.1; 70.5 (2C); 49.3; 49.1; 25.0

19.9. 8,10-Cyclic Tagitinyl Cyclic Trietter C: NMR: 123 15 .1-el p prx Tee. .; .Hz) '1.4 7 s 1 ... r, ii 1E ..' '.. 1.97 2.-51' 15_3 .2 - 4.35 4.1 :). 8 t 1.1 4.5 .3 x., 08 w 7.0 5.12 51 v 7.0 ti. rte` i, 5:91 2.7. Iü m x.11. . '; NMR: 200.7, 170.2, 136.7, 123.3, 96.6, 89.7, 76.6, 72.7, 51.2, 43.7, 20, 7, 20.3 1.15.2 Direct esterification of tagitinol C It is also possible to directly etherify tagitinol C, obtained for example enzymatically, according to the protocol described above (1.15.1 d). C-10-substituted 10-methoxy-tagitinin C was prepared from tagitinin C by methylation in the presence of methyl iodide according to a previously described protocol 10-methoxy-1 C-1-methyl-1 C-NMR: 124 o N.ft k: it TyType 1.91 7.0 s - 1.41 1.2 1.D d .w, 4.0 1..98 sot ci 2.87 #; 1 1 '= 4 .., 5..0 2.41 s _ 3 .2.5 3.4, .1. 8 5:22 Md 9.8, & Ci, 3_4 5.49 92 5.8 2 to 1.5 5..91 dt4 92 ,,. T.5 5.20 1.5: •. 33 s 4 .1 5..97 17.1 13 C NMR: 197.8 176.5, 160.0, 139.2, 137.9, 132.5;

124.6; 77.9; 76.9; 74.7; 51.7; 47.7; 47.1; 34.9; 23.0; 19.9; 19.2; 19.0.

1.17.C-14 Substituted Derivatives 14-tert-butyldimetylsilyloxy-tagitinin C angelate and 14-hydroxy-tagitinin C angelate are obtained from 14-hydroxy-rotundine, heliangolide extracted from Tithonia rotundifolia. After protection of the C-14 primary hydroxyl in tert-butyldimethylsilyl ether (by the action of TBDMSC1 in the presence of triethylamine in dichloromethane), then conversion of the protected heliangolide C-14 to germacranolide derivative, is obtained 14-tert-butyldimethylsilyloxy-tagitnyl C-angelate that can be deprotected with tert-butyl ammonium fluoride (TBAF) to give 14-hydroxytagitinin C angelate by methods described above. 14-tert-butyldimethylsilyloxy-tagitinyl C angellate 125 H NMR: i, .ppm Type (H CI.58 s D.Dg s 91 1.72 zU: Eri 1.5 .8 .. 7.3.1 ..5 1.28 d 0.9 1 .. 96 m - 2.56 13.7 .. 6.4 359 3.62 m 3.54 d 3..57 d 1G..l .39 ddd g..6.6ä. 3.1 5 ... 5.4 d .Bi 5.8 d 5.94 d .. 9.0, 1 ..4 5..G5 qq 7.3a ä4 6.22 5.5 d 17.4 5.79 13 C NMR: 198.3, 170.9, 167.2, 157.8, 139.7, 139.4, 138.8, 138.1, 131.9, 128.4, 124.6, 77.3, 75.7, 75.1; 69.9; 47.8; 43.2; 26.3 (3C); 20.4; 19.6; 19.0; 15.9; -5.2 (2C) 14-Hydroxy-tagitinyl C angellate 126 0 15 H NMR: Type 1..72 q.un 1.5 t3 cl, q : 1.5 1.88 d 0.9 2.51 _d 13..9, 6.3 3..52 d 11. 3 3.60 d g3 .6 3.62 el: 12, 1..7 5.40 ed 9: .9: to 5:54 d 3 9 5 ... S4 d t & 5.93 9.0,1: 4 5.66 '7: 3, .1: 4 6.22 d 6d 17.4 0.74 d 174 13 C 3M2: 198.3; 170.9; 167.2; 158.5; 139.7; 138.7; 138.0; (2C), 131.7, 128.3, 124.6, 77.3, 75.6, 75.5, 68.6, 47.8, 43.2, 20.5, 19.6, 15.9, 1.18.C-15 Substituted Derivatives The 15-carboxaldehyde-tagitinyl C angelate was obtained from 15-hydroxy-tagitinyl C angelate, extract of Helianthus annuus (sunflower), by oxidation with manganese dioxide. 15-Carboxaldehyde-tagitinyl C angelate OH 0 CH - HiCa, - ae = 0- {ÿ \ H 2 r 3 G :: ---- 1 H RMIV: 127 510 Dtel (ppm Type s e73 cui 1.5 '1.8 '3 TD 1: 105 eld 29 9.9 2.e; dd .2 6.3 MG 3..73 clq 3.'2; 1.8 .5..44 ddd 5.4, 3. 5.64 1.4: 5.91 1 .8: 5..W qq .2 6.28 d -L.5, .6,34 17.1 6.81 9.2 7.1.3 d 1 9.4 13 C NMR: 193.3, 190.8, 170.5, 165.0, 167.0, 152.4, 140.3;

140.0; 137.1; 131.0; 128.1; 125.5; 76.0; 75.4; 72.6; 49.3; 47.2; 28.6; 20.4; Similarly, 15-methoxy-tagitinyl C-angelate was obtained from 15-hydroxy-tagitinyl C-angelate by methylation in the presence of methyl iodide according to a previously described protocol. 15-Methoxy-tagitinyl C angellate 1H NMR: 128 o 10 Elel: the apprn X's Type z) 145 3 s 172 3. 1_87 3 dq 7.2, tA-2_08 dd 2A3 dd 44. ç1 133 3 s 157 br-. : s. 3.t, 6 brs. 19I d 4.26 d 125 54I ddd g.7,5_3,12 5.54, 9.2 d 1.2 5., 2 m _ 6.23 d 1 ..> 523. 17.1: 3..H 171 13 C NMR: 196.7; 170.8; 167.1; 162.8; 140.4; 139.7; 138.6; 137.7; 131.1; 128.3; 124.9; 76.7; 75.4; 72.7; 72.5; 58.9; 49.0; 47.8; 28.9; 20.5; 15.9. Finally, 15-acetoxy-tagitinyl C-angelate was obtained from 15-hydroxy-tagitinyl C-angelate by acetylation in the presence of acetyl chloride according to a previously described protocol. 15-Acetoxy-tagitinyl C angellate 1H RM1V: 129 -e X`s. Type J Hz 1.45 3 1.:2 1.47 {7.2a1. 1 2.0 t1d 3 ._ .. 1: s3.2 2.43 dci 1 3. c` 1. 3.13 b [5 -. . 4. ' 13.1 x`..34, s 1: .1 5.41 1 ddd 5.57 w _ wt 5.37 1.2 6.07 ry n 5:23 d 1.2 6.32 7.1 06, 4 17.1 13 C NMR: 196.0; 171.3; 167.1; 163.1; 140.3; 139.8; 138.4; 137.6; 130.8; 128.2; 125.0; 76.5; 75.4; 72.5; 64.5; 49.0; 47.6; 29.0; 21.0; 20.5; 15, 9.

EXAMPLE 2: Biological Tests The biological tests were carried out according to protocols described in the following articles: Ausseil F. et al. J. Biomol Screen. 2007, 12, 106-116 and Vandenberghe I. and

al. Biochemical Pharmacology 2008, 76, 453-462. In order to select new proteasome inhibitory compounds, it is necessary to indirectly measure the activity of this proteasome within the cells. For this purpose, we constructed a stable cell line, DLD-1 4Ub-Luc, derived from a human colon tumor line, producing a chimeric reporter protein called 4Ub-luc. This protein is a fusion between a 4 ubiquitin label and Luc luciferase. This label is able to address any protein that carries it to the proteasome. The 4Ub-Luc protein is therefore efficiently degraded by the proteasome unlike the unfused (wild) Luc protein. When the DLD-1 4Ub-Luc line is treated with a 130 1 proteasome inhibitor, the fusion protein is much less efficiently degraded and accumulates in the cell. This accumulation is detected by an increase in luciferase activity in the treated extract relative to the untreated cell extract. As a control, we verify that the inhibitor has no effect on the accumulation of wild Luc protein produced by the stable line DLD-1 RF. For the two lines and each product we determine an induction factor for the test product (or reference) corresponding to the ratio between the luciferase activities measured in the cells treated with this product (or reference) and the cells treated with the solvent. only. The activity of the product is then defined by its relative induction factor (i.e. ratio of its induction factor (luminescence IF) to that of the reference molecule which is epoxomycin (FI). = 1000) (see the data presented in the table below) Thus, the test set up by the Pierre-Fabre group is a cell test which has the advantage, compared to a purely enzymatic test, of not detecting that products able to enter the cell.

Operating procedure Two cell lines are used for this test: DLD-1 RF and DLD-1 4Ub-Luc. The culture medium used is as follows: MEM 5% fetal calf serum 5 ml penic streptomycin 2.5 ml fungizone 10 ml a-glutamine

Day 1: Inoculate 96 well white plates treated for culture, (with 600 μl of cell suspension at 1.105 c / ml per well). Incubate for 24 hours for the cells to adhere. On each plate 5 columns will be seeded by the DLD-1 4Ub-Luc and 5 others by the DLD-1 RF according to scheme 1 below.

Day 2: Remove the medium by inverting the plates on cotton wool, then perform the treatment with the compounds of the invention, the solvent alone or a reference compound such as epoxomycin. Each reference compound will be used at a concentration of 10 -5 M, whereas the compounds of the invention will be tested at concentrations of 10-6, 7.5.10-7, 5.10- and 2.5.10-7 M for period of 8 hours. Scheme 1: DLD-1 4Ub-Luc Line DLD-1 RF Line Columns are associated 2 to 2 (Examples 2 and 8, 3 and 9, 4 and 10 and 5 and 11), and are treated with the same compound. Columns 6 and 7 receive the controls of the experiment, namely 0.1% DMSO in the culture medium for wells B, C, D, and E of columns 6 and 7, and the positive control (epoxomycin 10- 'M) in the wells F and G.

After incubation, invert the plate on the wadding to empty the wells, rinse with 50 μl of PBS to remove all traces of the tested cytotoxic and then add 50 μl of Buffer Compound to test Control Control Compound to be tested Control Control Control Control Control passive lysis buffer (Passive Lysis Buffer, 5X, Promega ref .: E1941) diluted 1/5 in water. Stir vigorously for 5 to 10 minutes at room temperature on the plate shaker before freezing at -20 ° C.

Measurement of luciferase activity: The measurement is carried out using the Luciferase Assay System 10-Pack kit (Promega ref: E1501). On the day of measurement of luciferase activity, thaw the plates and wait until they have returned to room temperature. The optimal temperature for luciferase activity is between 20-25 ° C. Reconstitute the Firefly Luciferase substrate by thawing the buffer and place 10 ml of the buffer in the vial containing the lyophilized substrate. Wait until the solution is at room temperature before starting the assay, the light emission is quantified on the luminometer (put a white adhesive paper under the plate before reading to the luminometer).

Luminometer (Luminoskan, model RT). volume injected: 100pl integration time (total time): 15 seconds

The results obtained are as follows: Dose (M) Test product 10-6 7, 5.10- '5.10-' 2, 5.10- 'Tagitinine C 54 - 16.1 - 1113-13-Morpholino- 54.3 - 6.8 - Tagitinin C 14-Acetoxy-tagitinyl C 49.1 - 17.1 - Angelase Tagitinyl C benzoate 28.9 66.2 66.1 3.4 Tagitinyl C p-fluoro- 52.8 58.9 22.5 1, 7 4 benzoate Tagitinyl C cyclohexane 50.1 101 89.4 9.7 carboxylate 10-Methoxy-tagitine C 89.4 39.4 8.4 - Tagitinyl C senecioate 32.3 65.4 47.1 1.8 Tagitinyl C p-methoxy- 20.8 68.6 54.4 2.7 benzoate Tagitinyl C pent-4- 53.1 29.5 14.5 1.7 enyloate 14-t-Butyl-66,6 84,4 45, 2,6 2,6-Dimethylsilyloxy-tagitinyl C Angel Tagitinyl C Cyclohexyl 28.7 73 80.0 13 Acetate Tagitinyl C Cyclopropane 47.3 33.5 24.4 2 carboxylate Tagitinyl C adamantane 57.1 - 39.8 - carboxylate Tagitinyl C 4 -phenyl- 23.7 - 64.1 3.9 benzoate Tagitinyl c 33.7 - 54.4 1.8 cyclopentylpropyloate Tagitinyl C cyclopentane 52.8 - 24.2 1.6 carboxylate Tagitinyl C tiglate 1.0 3.9 44.6 Tagitinyl c Angelica 42.7 - 30.6 - Tagitinyl C 11.5 - 30.1 1.9 Methylacrylate Tagitinyl C 3-methyl-44.4-36.3 1.9 Butanoate 10-p-Methoxy-benzyloxy- 86.0 - 71.6 9.2.2 Tagitinyl C Cyclohexylcarboxylate 15-Acetoxy-tagitinyl C 3.3 8.5 30.8 22.2 angelate 15-Methoxy-tagitinyl C 7.3 17.2 58.6 21.7 angelate 8,10-di-p-69,1 - 51.5 3.6 Methoxybenzyloxy-tagitinyl C 10-p-Methoxybenzyloxy-8- 85.5 - 73.6 13.3 (p-methoxybenzyloxy) methoxy-tagitinyl C 8 -p-Methoxybenzyloxy-48,2-31, 9 1.8 Tagitinyl C 8,10-di-Benzyloxy-60,1-methyloxy-tagitinyl C

Claims (17)

REVENDICATIONS1. Compound of the following general formula (I): O R3 (I) and its pharmaceutically acceptable salts, isomers and isomeric mixtures in all proportions, in particular a mixture of enantiomers, and in particular a racemic mixture, for which: absent or represents a single bond, represents a single bond or a double bond, when Ai- -) represents A0, then A1O represents A-O, and Al represents a group CH, C-OR4, C-SR5 or CNR15R16, advantageously C-OR4 or C-SR5, and A2 represents a carbon atom, when Ai--O is absent, then A1O represents AI O, and A1 represents a carbon atom and A2 represents a group CH, C-OR6 or C- SR17, and preferably a C-OR6 or C-SR17 group, and more preferably a C-OR6 group, A3 represents a C = CH2 group or a CH-CH2R7 group, R represents a CH3, CH2F, CF3, CHF2 group. , CHO, CH2OH, CH2OR8, CH2OCOR8 or CH2OC (O) NR8, and preferably a CH3 group, CH2OR8 or CH2OCOR8, and more preferably CH3, - when the bond between carbons 1 and 2 is a double bond then R1 represents a hydrogen atom, 7 - when the bond ---- between carbons 1 and 2 is a single bond then R1 represents a hydrogen atom or a group OR9, SR10 or NR11R12, or R1 forms with R6 a bond connecting the carbon and oxygen atoms which carry them so as to form an epoxide between the carbons 1 and 10 R2 represents a hydrogen atom or a group OR13, where R2 forms with R6 a bond connecting the carbon and oxygen atoms which carry them so as to form an epoxide between the carbons 14 and 10, and - R3 represents a group -X-R14, X representing a group CO or C (O) N or a bond, with: - R4 representing a hydrogen atom or a (C 1 -C 6) alkyl group optionally substituted with one or more atoms of halogen, - R5 representing a group (C, -C6) alkyl optionally substituted with an OH or (C 1 -C 6) alkoxy group, - R 6 representing a hydrogen atom or a (C 1 -C 6) alkyl group, -CO- (C 1 -C 6) alkyl, aryl- (C 1 - C6) alkyl, benzyloxy- (C 1 -C 6) alkyl or SiRaRbR °, the (C 1 -C 6) alkyl unit of said group being optionally substituted by one or more halogen atoms and the aryl or benzyl unit of said group being optionally substituted; by a group (C 1 -C 6) alkoxy, or R 6 forming with R 1 a bond connecting the carbon and oxygen atoms which carry them so as to form an epoxide between the carbons 1 and 10, or R 6 forming with R2 a bond connecting the carbon and oxygen atoms that carry them to form an epoxide between carbons 14 and 10, or R6 and R14 together form a - (CH2) nO- (CH2) m- chain with n and m representing, independently of each other, an integer number of between 1 and 3, and preferably each representing 1, R7 representing a hydrogen atom or a g OR 18, SR19 or NR20Rz1, and preferably represents a group OR18, SR19 or NRz ° Rzl, representing a (C1-C6) alkyl group optionally substituted by one or more halogen atoms, R9 and R18 representing, independently the one of the other, a hydrogen atom or a (C 1 -C 6) alkyl group optionally substituted by one or more groups selected from a halogen atom and an OH, (C 1 -C 6) alkoxy, aryl and -O-CO- (C 1 -C 6) alkyl, R 10, R 17 and R 19 represent, independently of each other, a (C 1 -C 6) alkyl group optionally substituted with an OH, (C 1 -C 6) alkoxy group or -O-CO- (C 1 -C 6) alkyl, R 11 and R 12 represent, independently of one another, a hydrogen atom or an OH, (C 1 -C 6) alkyl or aryl- (C) group; -C6) alkyl, R11 and R12 not being able to represent at the same time an OH group, or R11 and R12 forming with the nitrogen atom which carries them a 5- or 6-membered heterocycle, possibly containing t, in addition to the nitrogen atom, one or more heteroatoms selected from oxygen, sulfur and nitrogen, and being optionally substituted with a (C 1 -C 6) alkyl group, R 13 representing a hydrogen atom or an O-protecting group, such as a (C 1 -C 6) alkyl group, -CO - ((C 1 -C 6) alkyl), SiRaRbR °, or -SO 2 -CF 3 R 14 representing a (C 1 -C 6) alkyl group, (C, -C6) epoxyalkyl, (C2-C6) alkenyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkyl- (C1-C6) alkyl, (C5-C10) polycycloalkyl, aryl- (C, -C6) alkyl, benzyloxy (C1-C6) alkyl, aryl or heteroaryl, the aryl, benzyl or heteroaryl unit of said group being optionally substituted by one or more groups selected from a halogen atom and a group (C, - C6) alkoxy, aryl or NR22R23,9-R15 and RI-6 representing, independently of one another, a hydrogen atom or an OH, (C1-C6) alkyl or aryl- (C1-C6) alkyl group, R15 and R16 can not represent at the same time an OH group, or R15 and R'6 forming with the nitrogen atom which carries them a 5- or 6-membered heterocycle, optionally comprising, in addition to the nitrogen atom, one or more heteroatoms chosen from oxygen, sulfur and a nitrogen, and being optionally substituted by a (C1-C6) alkyl group, - R20 and R2 'representing, independently of one another, a hydrogen atom or an OH, (C1-C6) alkyl or aryl- (C1-C6) alkyl, R20 and R2 'can not simultaneously represent an OH group, or R20 and Rn forming with the nitrogen atom which carries them a 5- or 6-membered heterocycle, optionally comprising, more than the nitrogen atom, one or more heteroatoms selected from oxygen, sulfur and nitrogen, and being optionally substituted by a (C1-C6) alkyl group, - R22 and R23 representing, independently of one of the another, a hydrogen atom or a (C1-C6) alkyl group, and - Ra, Rb and R ° representing, independently of one another, a (Cl-C6) alkyl group, excluding: - tagitinin C and tagitinin F, - compounds for which Ai - O represents C - O, AlO represents AT - O, the bond - between carbons 1 and 2 represents a single bond, A1 represents a C-OH group or C-OCH3r represents CH = CH2, R represents a CH3 group, R1 represents an OCH3 or OH group, R2 represents an atom of hydrogen and R3 represents a -C (O) CH (CH3) 2 or -C (O) C (CH3) = CHCH3r group and - compounds for which A2 - O is absent and A2 represents C - OH, A1O represents C = O, the bond between carbons 1 and 2 represents a double bond, A3 represents CH = CH2, R1 and R2 each represent a hydrogen atom and either R represents a group CH3 and R3 represents a group -C (O) CH (CH3) 2 or -C (O) C (CH3) = CHCH3r, where R is CH2OH and R3 is an O group 2. Compound according to claim 1, characterized in that it corresponds to the following formula (Ia): R2 Z1 OR3 (Ia) with Z1 representing a hydrogen atom or a group OR6 or SRI ', preferably an OR6 group or SRI-7 'and further preferably a group OR6, and R, R1, R2, R3, R6, R'7, A3 and - being as defined in claim 1. 3. Compound according to claim 1, characterized in that it corresponds to the following formula (Ib): ## STR1 ## with Z 2 representing a hydrogen atom or a group OR 4, SR 5 or NR 15 R 16, and preferably a group OR4 or SRS, and R, R1, R2, R3, R4, R5, R15, R16, A3 and as defined in claim 1. 4. Compound according to any one of claims 1 to 3, characterized in that: R1 represents a group OR9, SR10 or NR11R12 and / or A3 represents a group CH-CH2R7 with R7 representing a group OR18, SR19 or NR2 ° R 21,, R is CH 3, R 2 is hydrogen, and R 3 is -CO (C 1 -C 6) alkyl, and preferably -CO-CH (CH 3) 2, with A, , A2, R9, R1, R11, R12, R1, as defined in claim 1. 5. Compound according to any one of claims 1 to 4, characterized in that R3 represents: ## STR2 ## being a group R14 with R14 as defined in claim 1, or a group COR24, with R24 representing a grouping (C3 -C 7) cycloalkyl, (C 3 -C 7) cycloalkyl- (C 1 -C 6) alkyl, (C 5 -C 10) polycycloalkyl, aryl- (C 1 -C 6) alkyl, benzyloxy- (C 1 -C 6) alkyl, aryl or heteroaryl, the aryl, benzyl or heteroaryl unit of said group being optionally substituted by one or more groups selected from a halogen atom and a (C 1 -C 6) alkoxy, aryl or NR 22 R 23 group, A3 represents a C = CH 2 or CH group; -CH2-NR2 ° R21, R is CH3, CH2OC (O) CH3 or CH2OCH3, and R20, R212 - R2 represents a hydrogen atom, and R1 represents a hydrogen atom and the bond between the carbons 1 and 2 is a double bond with Al, A2, Rzo, R21, Rzz, Rzs, and - as defined in claim 1. 6. Compound according to one of claims 1 to 5 characterized in that it is selected from: EtO Pro BuO HO iPrO HO "EtS HO" 3 CI3CCH2O "'HO CF3CCH2O" HO OH4 O OCOiPr ON HOC ~ CHZC6H5 HO " "OCOiPr HOC ~ CHZC6H5 N HO" "OMe OH OMe6 OMe - 0 OO OMe and7 7. Compound according to any one of claims 1 to 6 for its use as a medicament, in particular for the treatment of cancer. 8. Pharmaceutical composition comprising at least one compound according to any one of claims 1 to 6 in association with a pharmaceutically acceptable carrier. 9. Pharmaceutical composition according to claim 8, characterized in that it further comprises at least one other active ingredient, preferably an anti-cancer agent, advantageously chosen from 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine. , 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserel formestane, aminoglutethimide, anastrazole, letrozole, tamoxifen, octreotide and lanreotide. 10. Pharmaceutical composition comprising: (i) at least one compound according to any one of claims 1 to 6, and (ii) at least one other active ingredient, advantageously chosen from anti-cancer agents such as 6-mercaptopurine, fludarabine , cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocine, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goser line, buserelin, formestane, aminoglutethimide, anastrazole, letrozole, tamoxifen, octreotide or lanreotide. as combination products for simultaneous, separate or spread use over time. 11. Composition according to any one of claims 8 to 10 for its use as a medicament for the treatment of cancer. 12. A process for the synthesis of a compound of formula (I) as defined in claim 1, wherein R1 represents a group OR9, SR10 or NR11R12 and / or A3 represents a group CH-CI-12R7, with R7 representing a group OR18, SR19 or NR20R21, and R9, R ', R11, R12, R18, R19, R2 ° and Rn as defined in claim 1, characterized in that the compound of formula (I) is prepared by a reaction of Michael between a compound of formula (II) below: R2 for which Al, A2, R, R2, R3, and - are as defined in claim 1 and a nucleophile of formula R1H and / or R7H, with R1 and R7 as defined above. 13. Process for synthesizing a compound of formula (Ie) below: and its pharmaceutically acceptable salts, isomers and isomeric mixtures in all proportions, in particular a mixture of enantiomers, and in particular a racemic mixture, for which: is absent or represents a single bond, - represents a single bond or a double bond, when Ai- -O represents A0, then A4O represents A4 O, and A4 represents a C-OH group, and A2 represents a carbon atom, when Al-O is absent, then A4O is A4 O, and A4 is a carbon atom and A2 is a group C-OR6, and R6 and R3 are as defined in claim 1, 149 (Ie) 0 from tagitinin C of the following formula: characterized in that the process comprises the following successive steps. (1) optionally protecting the carbonyl function at the 3-position and / or protecting the C = CH 2 double bond at the 11-13 position, (2) hydrolyzing the isopropyl ester at the 8-position to give the corresponding alcohol, (3) ) conversion of the alcohol obtained in the preceding step (2) into a group OR 3, and optionally conversion of the alcohol in position 10 to an OR 6 group when R 6 does not represent a hydrogen atom, (4) optionally deprotection of the carbonyl function in position 3 and / or deprotection of the double bond in the 11-13 position, and (5) isolation of the compound (Ie) thus obtained. 14. Compound of formula (IIIa) or (IIIb) below: (IIIa) or R1 OH OH and its pharmaceutically acceptable salts, its isomers and mixtures of isomers in all proportions, in particular a mixture of enantiomers, and in particular a racemic mixture, for which: represents a single bond or a double bond, - R1 represents a hydrogen atom when it represents a double bond or represents a hydrogen atom or a group OR9, SR10 or NR "R12, with R9, R'O, R11 and R'2 as defined above, when - - represents a single bond, A5 represents a group C = O, CH-OH or CH-OGP1, where GP1 represents an O-protecting group such that a group SiRaRbR °, with Ra, Rb and R ° representing, independently of one another, a (C 1 -C 6) alkyl group, - A 6 represents a group C = CH 2 or CH-CH 2 GP 2, where GP 2 represents a protecting group of activated bonds such as an imidazolyl or morpholinyl radical, A7 represents an atom of h or an OH or OGP3 group, wherein GP3 represents an O-protecting group such as a (C1-C6) alkyl or SiRdReRf group. 15. Compound according to claim 14, characterized in that it is chosen from: OH OH OH HO HO HO HO MeO 'HO' and 16. Process for the preparation of a compound of formula (IIIa) or (IIIb) as defined in claim 14 wherein R1 represents a hydrogen atom and represents a double bond, starting from tagitinin C of the following formula: Characterized in that the method comprises the following successive steps. (a) optionally protecting the enone function at position 1-3 and / or protecting the C = CH 2 double bond at position 11-13, (b) hydrolyzing the isopropyl ester at position 8 to give the corresponding alcohol (c) optionally deprotecting the enone function at the 1-3 position and / or deprotecting the double bond in position 11-13, and (d) isolating the compound (IIIa) or (IIIb) thus obtained. 17. The process as claimed in claim 16, characterized in that step (b) is carried out enzymatically, in particular in the presence of an esterase such as crude porcine liver esterase or liver horse esterase.