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Definitions

• Zaragócico and derivatives thereof and intermediates of said synthesis. It also refers to the use of said intermediates in the synthesis of Zaragócic acid.
• Zaragócic acid A (IA, Figure 1). It was simultaneously isolated between 1991 and 1992 by three independent groups: the Merck group called it Zaragócico A acid, while the Glaxo and the Tokyo University groups Noko / Mitsubishi Kasei Corporation called it S 1.
• WO 93/16066 and WO 93/17557 describe the isolation of derivatives of Zaragócicos acids from different fungal cultures. It also shows the chemical modification of the compounds obtained and their usefulness as cholesterol lowering agents. Also in WO 94/04144 various analogues of Zaragócic acids are disclosed, as well as their inhibitory activity of the enzyme squalene synthase. Zaragócicos acids have in their structure a common bicyclic grouping 2,8-dioxabicyclo [3.2.1] octane (rings A and B, Figure 1), which has 6 consecutive stereo center s (carbons C3, C4, C5, C6, C7 and Cl), three of them quaternary (Cl, C4 and C5 carbons). The structural difference between the members of the Zaragócicos acid family lies in the different substituents R and Y R x (see Figure 2) presenting in positions C6 and Cl, respectively, of the common bicyclic skeleton. ring A
• Zaragócicos acids Due to the important biological activity that they present, as useful agents in cholesterol reduction, and their high structural complexity, Zaragócicos acids have attracted the attention of numerous research groups. To date, three total synthesis of Zaragócic acid A (IA) have been described in the literature.
• Dr. Nicolaou [a) Nicolaou, K. C; Yue, EW; Naniwa, Y .; De Riccardis, F .; Nadin, A .; Leresche, JE; La Greca, S .; Yang, Z. Angew. Chem. Int. Ed. Engl. 1994, 33, 2184-2187; b) Nicolaou, K.
• a first aspect of the present invention is directed to a process for obtaining a compound of formula (I), its enantiomers or mixtures thereof, characterized in that it comprises reacting in acidic medium a compound of formula (II), its enantiomers or mixtures thereof, or a compound of formula (III), its enantiomers or mixtures thereof, or a mixture of compounds of formula (II) and (III). Additional aspects of the invention are directed to compounds of formula (I),
• a further aspect of the present invention is directed to a process for the preparation of zarazoic acid and derivatives thereof of formula (XXVI), its stereoisomers, especially enantiomers, or mixtures thereof, characterized in that it comprises the steps
• a further aspect of the present invention is directed to the use of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIIa), (VIIb ), (VIII), (VIIa), (VIIIb), (IX), (IXa), (IXb), (X), (XI), (XII), (XIII), (XIV), (XV) and / or (XVI), its stereoisomers, especially enantiomers, or mixtures thereof, for the synthesis of zarazoic acid and derivatives thereof, of formula (XXVI), its stereoisomers, especially enantiomers, or mixtures thereof.
• a first aspect of the present invention is directed to a process for obtaining a compound of formula (I), its enantiomers or mixtures thereof
• R is selected from the group consisting of C1-C20 alkyl and C 1 -C 20 alkenyl, which are unsubstituted or substituted in any position by at least one group selected from the group consisting of C1-C4 alkyl, alkylidene C 1 -C3, C 1 -C 3 alkylcarboxyhydroxy, hydroxyl and protected hydroxyl; and / or substituted by a group at the terminal position of the chain selected from the group consisting of C 6 -CiO aryl, 5- or 6-membered mono- or bicyclic heteroaryl in each ring, which may be unsubstituted or substituted.
• R 3 , R 4 and R 5 are independently selected from the group of C1-C3 alkyl; characterized in that it comprises reacting in acidic medium a compound of formula (II), its enantiomers or mixtures thereof, or a compound of formula (III), its enantiomers or mixtures thereof, or a mixture of compounds of formula (II) Y
• R 2 , R 3 , R 4 and R 5 are as defined above; and R 6 is a C1-C3 alkyl group.
• R 3 and R 4 are the same, more preferably R 3 , R 4 and R 5 are the same, preferably methyl.
• the compounds of formula (II) and (III) already contain all the stereocenters of zarazoic acid and its derivatives. Without wishing to be bound by theory, it seems that in the first place the OR 6 group is lost with the simultaneous or subsequent formation of an oxonium ion and subsequent rearrangement to form a compound of formula (I). Therefore, the formation of the compounds of formula (I) is independent of the stereochemistry in the acetal position of the tetrahydrofuran ring of the compounds of formula (II) and (III).
• the acidic medium comprises the addition of an inorganic protic acid, for example, HCl, H 2 SO 4 or HNO 3.
• the acidic medium is a dilute acidic medium, preferably in a volume concentration with respect to the total volume of the reaction between 0.1 and 20%, more preferably between 0.5 and 10%, more preferably between 1 and 5 %.
• the solvent is an alcohol of formula R 6 OH.
• the reaction is performed at a temperature between 0 and 100 0 C, more preferably between 25 and 9O 0 C, more preferably between 50 and 8O 0 C.
• the reaction is conducted in a sealed container (for example, a Kimble ®). Additional aspects of the present invention are the compounds of formula
• a further aspect of the present invention is directed to a process for the synthesis of a compound of formula (II), its enantiomers or mixtures thereof, or of a compound of formula (III), its enantiomers or mixtures thereof , characterized in that it comprises the dihydroxylation of a compound of formula (IV), its enantiomers or mixtures thereof
• R 6 is a C1-C3 alkyl group.
• dihydroxylation reaction is a reaction widely used in the synthesis of organic molecules and can be carried out under conditions known to the expert, as described in Smith, MB; March, J. March 's Advanced Organic Chemistry; Jonh Wiley & Sons: New York, 2001. pp .: 1048-1051.
• dihydroxylation is carried out in the presence of osmium tetroxide / iV-oxide-iV-methylmorpholine or potassium permanganate. More preferably, the hydroxylation is carried out in the presence of RuCIsZNaIO 4 (for useful conditions to effect this transformation, see a) Shing, TKM; Tai, VW -F .; Tam, EKW Angew. Chem. Int.
• the process comprises dihydroxylating in the presence of RuCl 3 a compound of formula (IVa), its enantiomers or mixtures thereof, to give a compound of formula (II), its enantiomers or mixtures thereof
• R 2 , R 3 , R 4 and R 5 are as defined above; and R 6 is a C1-C3 alkyl group.
• the process comprises dihydroxylating in the presence of RuCl 3 a compound of formula (IVb), its enantiomers or mixtures thereof, to give a compound of formula (III), its enantiomers or mixtures thereof
• R 2 , R 3 , R 4 and R 5 are as defined above; and R 6 is a C1-C3 alkyl group. Therefore, another aspect of the present invention is directed to compounds of formula (IV), (IVa) or (IVb) their stereoisomers, especially their enantiomers, or mixtures thereof as defined above, which are intermediates that they allow access to the compounds of formula (I), their enantiomers or mixtures thereof, and therefore, also to the zaragócic acid and its derivatives of formula (XXVI).
• a further aspect of the present invention is directed to a process for the synthesis of a compound of formula (IV), its stereoisomers, especially its enantiomers, or mixtures thereof, which comprises the acid treatment of a compound of formula ( V), its stereoisomers, especially its enantiomers, or mixtures thereof
• R 2 , R 3 , R 4 and R 5 are as defined above; and each of R 7 and R 8 is independently selected from the group consisting of hydrogen, C1-C4 alkyl and C ⁇ -Cio aryl; or R 7 and R 8 , together with the carbon atom to which they are attached, form a C2-C7 alkylidene group.
• the reaction is carried out in the presence of para-toluenesulfonic acid (p-TsOH).
• the solvent is an alcohol of formula R 6 OH, more preferably also of formula R 4 OH.
• Another aspect of the present invention is directed to a compound of formula (V) its stereoisomers, especially its enantiomers, or mixtures thereof as defined above, intermediates useful for the synthesis of zarazoic acid and its derivatives formula (XXVI).
• a further aspect of the present invention relates to a process for the synthesis of a compound of formula (V), its stereoisomers, especially its enantiomers, or mixtures thereof, characterized in that it comprises
• R 2 , R 3 , R 5 , R 4 , R 7 and R 8 are as defined above; Y
• R 9 is a trialkylsilyl group
• ethyl acetate is used as the solvent and in the reaction workup the excess reagent, as well as the by-products derived therefrom, can be removed by filtration once the reaction is over.
• ethyl acetate is used as the solvent and in the reaction workup the excess reagent, as well as the by-products derived therefrom, can be removed by filtration once the reaction is over.
• a further aspect of the present invention is directed to a process for the synthesis of a compound of formula (VII), its stereoisomers, especially its enantiomers, or mixtures thereof, which comprises reacting a compound of formula (VIII), its enantiomers , or mixtures thereof, with a compound of formula (XX)
• R 2 , R 3 , R 5 , R 4 , R 7 , R 8 and R 9 are as defined above; and each of the groups Ar is independently selected from among aryl groups C 6 -Ci 0 .
• the preparation of the ilide of formula (XX) can be carried out in accordance with conditions known in the state of the art (Villa, MJ; Warren, SJ Chem. Soc. P. T 1 1994, 12, 1569-1572) or commercially acquired .
• said ilium is [(methoxycarbonyl) methylene] triphenylphosphorane.
• the compounds of formula (VII), their stereoisomers, especially their enantiomers, or mixtures thereof are compounds of formula (VIIa) or (VIIb), their stereoisomers, especially their enantiomers, or mixtures thereof
• the compounds of formula (VIII), their stereoisomers, especially their enantiomers, or mixtures thereof are compounds of formula (Villa) or (VIIIb), their stereoisomers, especially their enantiomers, or mixtures of the same
• said transformation is performed under the conditions described in Shi, Y. -J .; Hughes, DL; McNamara, JM Tetrahedron Lett. 2003, 44, 3609-3611, which is incorporated in its entirety by reference, more preferably in the presence of diethylazodicarboxylate (DEAD) / triphenyl phosphine (TPP).
• said compound of formula (VIII), its enantiomers, or mixtures thereof is obtained by oxidizing, preferably in the presence of IBX, a compound of formula (IX), its enantiomers, or mixtures thereof.
• Another aspect of the present invention is directed to compounds of formula (VIII) or (IX), their enantiomers, or mixtures thereof as defined above, which are intermediates that allow access to the zaragócic acid and its derivatives of formula (XXVI).
• the compound of formula (IX), its enantiomers or mixtures thereof is a compound of formula (IXa) or (IXb), its enantiomers or mixtures thereof:
• a further aspect of the present invention is directed to a process for the synthesis of a compound of formula (IX), its enantiomers, or mixtures thereof, characterized in that it comprises the dihydroxylation, preferably in the presence of OsO 4 , of a compound of formula (X), its enantiomers, or mixtures thereof
• R 2 , R 3 , R 4 , R 7 , R 8 and R 9 are as defined above.
• the dihydroxylation of the compounds of formula (X) can proceed by attack by the alpha or beta face, giving rise to two possible compounds of formula (IX), their enantiomers or mixtures thereof, specifically compounds of formula (IXa) or (IXb ), their enantiomers or mixtures thereof, mentioned above.
• R 2 , R 3 , R 4 , R 7 , R 8 and R 9 are as defined above.
• the protection of the 1,2-diol group of a compound of formula (XI) as acetal or hemiacetal can be carried out following methods known in the state of the art and allows to maintain this stable group throughout the synthesis.
• Examples of conditions for the protection of 1,2-diols useful in the present invention see a) Konno, H .; Makabe, H .;
• R 7 and R 8 are methyl, or hydrogen or phenyl; or together with the carbon to which they are attached they form a cyclohexane or cyclopentane ring.
• R 7 is methyl and R 8 is phenyl.
• a compound of formula (XI), its enantiomers, or mixtures thereof, is reacted with 2,2-dimethoxypropane in the presence of catalytic amounts of acid, preferably paratoluenesulfonic acid.
• another aspect of the present invention is directed to a compound of formula (XI) its enantiomers, or mixtures thereof as defined above, which are intermediates that allow access to the zaragócic acid and its derivatives of formula ( XXVI).
• a further aspect of the present invention is directed to a process for the synthesis of a compound of formula (XI), its enantiomers, or mixtures thereof, characterized in that it comprises the following steps (i) reacting a compound of formula (XXI) in the presence of a compound of formula PY3, and the subsequent addition of a compound of formula (XVI), its stereoisomers or mixtures thereof, to give a compound of formula (XV), its stereoisomers or mixtures thereof
• the epoxidation of the compounds of formula (XV) can be carried out in the presence of epoxidizing agents such as metachloroperbenzoic acid, resulting in a compound of formula (XIV) in racemic form.
• epoxidation can be carried out by chiral reagents, resulting in compounds of formula (XIV) enantiomerically pure or enantiomerically enriched, which results in subsequent intermediates of formula (XIII) to (I) and (XXV) and ( XXVI) (defined below) are also obtained enantiomerically pure or enantiomerically enriched.
• a chiral epoxidant agent makes it possible to obtain the enantiomerically pure or enantiomerically enriched formula (XXVI).
• Some useful conditions for carrying out epoxidation enantiomerically may found in Jacobsen-Katsuki (see: Katsuki, T. Adv. Synth. Catal. 2002, 344, 131-147) 2); or Shi (see: Wang, ZX; Tu, Y .; Frohn, M .; Zhang, J. R; Shi, YJ Am. Chem. Soc. 1997, 119, 11224-11235).
• step (iii) allows to open the epoxide and isomerize the double bond to provide a compound of formula (XIII).
• the base used is DBU (l, 8-diazabicyclo [5.4.0] undic-7-eno).
• Non-limiting examples of conditions under which the hydroxyl group of a compound of formula (XIII) (step (iv)) can be protected to obtain a compound of formula (XII) can be found in, for example, Dalla, V .; Catteau, JP Tetrahedron 1999, 55, 6497-6510, and trialkylsilyl groups that can be used in this reaction, as well as reagents suitable for introduction and removal, are known to the person skilled in the art (eg see Greene, TW; Wuts, PGM Greene 's Protective Groups in Organic Synthesis; John Wiley & Sons: Hoboken, 2007).
• the base used is imidazole and the silylating agent is TBDMSCl (tert-butyldimethylsilyl chloride).
• the silylating agent is TBDMSOTf (tert-butyldimethylsilyl trifluoromethasulfonate).
• dihydroxylation can be carried out under conditions known to the expert, as described in Smith, M. B .; March, J. March 's Advanced Organic Chemistry; Jonh Wiley & Sons: New York, 2001. pp .: 1048-1051.
• the dihydroxylation is carried out in the presence of osmium tetroxide / iV-jV-methylmorpholine or potassium permanganate. Therefore, additional aspects of the present invention are directed to compounds of formula (XII), (XIII), (XIV) or (XV), their enantiomers, or mixtures thereof as defined above, which are intermediate which allow access to zaragócic acid and its derivatives of formula (XXVI).
• R 2 is as defined above;
• R 1 is selected from the group consisting of C1-C20 alkyl or Ci-C 2 O alkenyl, which are unsubstituted or substituted by at least one group selected from the group consisting of Ci-C 4 alkyl; and / or a group in the terminal position that is selected from the group consisting of C ⁇ -Cio aryl;
• Z is selected from the group consisting of hydroxyl and alkoxy; and
• R 2 is as defined above.
• Non-limiting conditions for the purposes of the present invention are preferably those in which the hydrolysis of the compounds of formula (XXV) is carried out in the presence of an alkali metal or alkaline earth metal hydroxide, for example in the presence of LiOH, NaOH, Ba (OH) 2 , or in the presence of Na 2 S.
• Coupling of the compound of formula (XXII) involves esterification of the compound of formula (XXV) to provide the compound of formula (XXVI).
• the sequence described in the present invention makes it possible to obtain the zarazoic acid and derivatives thereof of formula (XXVI), in a few steps, using reagents customary in the synthesis of organic compounds.
• Said synthesis can be carried out by carrying from the beginning (compounds of formula (XVI)) the complete chain R 2 .
• the sequence can be performed as described above, and at the most convenient time to construct the complete chain, either by a single synthetic stage, or by successive consecutive or non-consecutive stages.
• the compound of formula (XVI) can be constructed from the beginning with all the functionalities of the final compound of formula (XXVI). For example, by reacting the compound of formula (XXX) with compound 32 described in Carreira, et al, J. Am. Chem. Soc. 1995, 117, 8106-8125 following a procedure analogous to that shown in Figure 3 , would provide the compound of formula (XVI) necessary to obtain, for example, zaragócic acid C (see Figure 4). compound 32 described in Carreira et al compound of formula (XVI) necessary
• Alkyl refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, which does not contain unsaturation and is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, propyl , isopropyl or «-butyl.
• Alkenyl refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, which contains at least one unsaturation, and which is attached to the rest of the molecule by a single bond, for example, ethenyl, n -propenyl, i-propenyl, n-butenyl, n-pentenyl, etc.
• Alkylidene refers to a linear hydrocarbon chain radical consisting of carbon atoms and hydrogen, and which is attached to the rest of the molecule from both ends by simple bonds to the same carbon atom, and therefore form a cycle , for example, ethylene (-CH 2 -CH 2 -), n-propylene (-CH2-CH2-CH 2 -), n-butylene (-CH2-CH 2 -CH2-CH 2 -), n-pentylene ( -CH 2 -CH2-CH2-CH2-CH 2 -), etc.
• Halide or "halogen” means -F, -Cl, -Br or -I;
• Enantiomer means the mirror image of a stereoisomerically pure compound.
• an enantiomer can be considered as a mixture of two enantiomers having an enantiomeric excess greater than 95%, preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%.
• Aryl refers to an aromatic hydrocarbon radical such as phenyl, or naphthyl.
• Arylalk refers to an aryl group attached to the rest of the molecule through an alkyl group, for example, benzyl ("- (CH2) -phenyl” or "Bn").
• Alkoxy refers to a radical of the formula -OR 10 , wherein R 10 represents a group selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, and substituted arylalkyl or not replaced
• Such groups are known to the person skilled in the art and can select the most appropriate ones based on the reactions to which you want the hydroxyl group to be inert and / or the conditions under which you want to eliminate said protecting group, that is, the conditions under which you want to deprive the hydroxyl group.
• suitable hydroxyl protecting groups and their removal conditions can be found in reference texts such as Greene and Wuts'"Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., New York, 4th Ed. , 2007.
• the oxygen atom can be replaced by a sulfide atom to form an alkylthiomethyl ether of formula -CH 2 -SR 12 , such as methylthiomethyl ether.
• Tetrahydropyranyl ethers and derivatives are also commonly used hydroxyl protecting groups;
• C 10 -C 15 alkyl refers to an alkyl group of ten, eleven, twelve, thirteen, fourteen or fifteen carbon atoms, such as decyl, undecyl, dodecyl, tridecyl, tetradecyl or pentadecyl.
• the compounds of the invention also refer to those that include compounds that differ only in the presence of one or more isotopically enriched atoms.
• the compounds having the present structures except for the substitution of a hydrogen for a deuterium or for tritium, or the substitution of a carbon for a carbon enriched in 13 C or 14 C, are within the scope of this invention. .
• the 1 H and 13 C nuclear magnetic resonance spectra were performed at room temperature in the solvent indicated in each case (CDCI3 and CD3OD) using the following devices: Varies Gemini-200 (200 MHz), Varies INOVA- 300 (300 MHz), Bruker Advance-300 (300 MHz) and Vary INOVA-400 (400 MHz).
• the values of chemical shifts are expressed in parts per million ( ⁇ , ppm), using the residual solvent signal as internal reference: CDCl 3 , 7.26 ppm ( 1 H-NMR) and 77.0 ppm ( 13 C-NMR); CD 3 OD, 3.31 ppm ( 1 H-NMR) and 49.0 ppm ( 13 C-NMR).
• the product was purified by chromatographic column (hexane / AcOEt, 20: 1), obtaining (5.03 g, rto. 71%) (3E, 5E) -3- (methoxycarbonyl) -3,5-methyl tridecadienoate (58), As a transparent oil.
• LRMS m / z 298 (M + , 0), 282 (0), 266 (1), 237 (2), 206 (2), 179 (3), 170 (100), 139 (10) , 111 (80).
• LRMS m / z 486 (M + , 0), 471 (4), 455 (0), 429 (44), 411 (6), 397 (1), 371 (7), 339 (34) , 321 (3), 311 (7), 279 (7), 243 (100), 156 (36).
• Example 8 Preparation of rac- (Z, 4S, 5 / ?, 6 / ?, 7S) -7- (phosphr-butyldimethylsilyloxy) -5,6- (dimethylmethylenedioxy) -4-hydroxy-3,4-bis (methoxycarbonyl) ) Methyl -2-tetradecenoate (76 «)
• the mixture was heated at 80 0 C for 7 hours. After that time the mixture was filtered under vacuum over Celite and the solvent was removed under reduced pressure.
• the product was purified by chromatographic column (hexane / AcOEt, 4: 1), obtaining (0.1 10 g, rt. 63%) rac- (Z, 45 ', 5i?, 6i?) - 5,6- (dimethylmethylenedioxy) Methyl -4-hydroxy-3,4-bis (methoxycarbonyl) -7-oxo-2- tetradecenoate (11 Oa), as a colorless oil.
• the product was purified by chromatographic column (hexane / AcOEt, 4: 1), obtaining (0.160 g, rto. 74%) rac- (2Z, AR, 5R, 6R) -5, ⁇ - (dimethylmethylenedioxy) -4-hydroxy -3,4-bis (methoxycarbonyl) -7-oxo-2-t methyl etradecenoate (1106), as a colorless oil.
• the product was purified by chromatographic column (hexane / AcOEt, 3: 1), obtaining (0.030 g, rto. 71%) rac- (Z, 45 ', 5i?, 6i?, 75) -5,6-dihydroxy- Methyl 4,7-epoxy-7-methoxy-3,4-bis (methoxycarbonyl) -2-tetradecenoate (Illa) and (0.01 1 g, rto.
• Example 14 Reaction of rac- (Z, 4S, 5 / f, 6 / f, 7S) -5,6-dihydroxy-4,7-epoxy-7-methoxy-3,4-bis (methoxycarbonyl) -2- methyl tetradecenoate (Illa) with OsO 4
• LRMS m / z 385 (1), 355 (1), 335 (11), 303 (1), 290 (2), 278 (4), 247 (15), 217 (4), 159 ( 40), 101 (15), 83 (100).
• Example 14 Reaction of rac- (Z, 4S, 5 / f, 6 / f, 7S) -5,6-dihydroxy-4,7-epoxy-7-methoxy-3,4-bis (methoxycarbonyl) -2- methyl tetradecenoate (Illa) with RuCWNaIO 4
• Example 15 Reaction of rac- (Z, 4S, 5 / ?, 6 / ?, 7 /?) - 5,6-dihydroxy-4,7-epoxy-7-methoxy-3,4-bis (methoxycarbonyl) - Methyl 2-tetradecenoate (112 «) with RuCWNaIO 4
• LRMS m / z 466 (M + , 0), 385 (2), 375 (3), 367 (4), 335 (11), 315 (6), 275 (4), 247 (15) , 229 (26), 185 (22), 159 (100), 127 (49).

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