MXPA97008005A - Asymmetric epoxides, their synthesis and - Google Patents

Abstract

A process for preparing chiraloptimetically enriched epoxide of the formula (I), wherein R1, R2 and R3 are each independently selected from H, R, R-CO- and RO-CO, each R independently being substantially a hydrocarbon group of up to 20 carbon atoms, and X is an alkyl or cycloalkyl group of up to 10 carbon atoms, with the proviso that -CO-X is not enolizable, which comprises the asymmetric epoxidation of a corresponding prochiral alkene of the formula (II): R1R2C = CR3-CO-X, by reaction of an oxidant in the presence of a chiral catalyst. Many epoxies enriched optically (I) are novel

Description

ASYMETRIC EPQXT.PQS, ITS SYNTHESIS AND USE DESCRIPTION OF THE INVENTION This invention relates to epoxides, their synthesis by asymmetric epoxidation of enones, and their use. Enantioselective epoxidation of prochiral alkenes is a valuable methodology, which allows two stereogenic centers to be created in a simple synthetic operation. These established methods tend to be limited to specific classes of substrate. The best known is titanium tartrate catalyzed epoxidation of allylic alcohols, which is first reported by Sharpless as a stoichiometric method, in Katsu i et al, J. Am. Chem. Soc. (1980) 102: 5974 and subsequently adapted into a catalytic variant: see Gao et al. J. Am. Chem. Soc. (1987) 109: 5765. More recently, epoxidations using chiral (exits) Mn (III) catalysts have been applied to a variety of alkene substrates, both functionalized and functionalized; see Jacobsen, chapter 4.2 in Catalytic Asymmetric Synthesis, ed. I. Ojima (1993) VCH, New York. Although both known processes are approved as generic methodologies for laboratory-scale synthesis, confidence in catalysts based on metals and reagents means that the operation on a large scale can be disadvantageous in terms of cost, process of elaboration and disposal of effluents. A third and potentially more economical methodology is the use of metal-free synthetic polypeptides, such as poly-L-leucine as catalysts for the asymmetric epoxidation of α, β, unsaturated, prochiral ketones of the general formula to give the corresponding optically enriched epoxies O RVC-CR -CO-X (I) This process was first reported by Julia et al, Angew. Chem. Int. Ed. Engl. (1980) 19: 929. However, it is reported that high enantioselectivities are confined to trans-caleona derivatives; see Julia et al, J. Chem. Soc., Perkins Trans. 1 (1982) 1317; Colonna et al, Tetrahedron (1983) 39: 1635; Banfi et al, Tetrahedron (1984) 40: 5297; Baures et al., Tetrahedron Lett. (1990) 31: 6501; and Itsuno et al, J. Org. Chem. (1990) 55: 5047. In this way, this reaction has been considered to be of limited scope in organic synthesis. The optically enriched epoxides are especially suitable for nucleophilic ring opening reactions to give, in a stereocontrolled mode, products that carry heteroatom functionality on adjacent chiral centers. In this regard, the syntheses of (2R, 3S) -sin-3-phenylisoserine are reported by Boa et al, Contemporary Organic Synthesis (1994) 1:47 and references thereof. Several methods proceed via the trans- or cis-phenylglycidate intermediates, prepared by the enantioselective oxidation (epoxidation and dehydroxylation) of styrene derivatives; see Greene, J. Org. Chem. (1990) 55: 1957; Jacobsen, J. Org. Chem. (1992) 57: 4320; and Sharpless, J. Org. Chem. (1994) 59: 5105. Although this is an effective total strategy, the provision of enantiopure phenylglycides relies on the metal-based epoxidation methodologies described above, and aspects of downstream chemistry are not well suited for large-scale operation. The compounds of formula I are known in racemic form. For example, compounds wherein R1 is phenyl, R2 and R ^ are each H, and X is t-butyl or cyclopropyl, are described in EP-A-0336841 and OA-0113066, and by Matano, J. Chem Soc. Perkin Trans. I. (1994) 2703, Meth-Cohn, ib. 1517 and Treves, JACS (1967) 89: 6257. The nature of the functional groups makes such compounds difficult to separate into constituent enantiomers, by conventional resolution techniques. An optically enriched epoxide of formula I (R1 = CF3, R2 = R3 = H, X = t-butyl) is reported by Lin et al, J. Fluorine Chem. (1989) 44.:113-120. Its synthesis is from 1, 1, 1-trifluoro-2-hidroxi-5, 5-dimetilhexan-4-one enriched optically, using lithium diisopropylamide. This is not a commercial process. Corey et al., Tetrahedron Lett. (1991) 32: 2857, reports the t-butyl glycidate 5 (see Scheme 1) as the product of a chiral Darzens reaction between t-butyl bromoacetate and benzaldehyde. It has been surprisingly discovered that asymmetric epoxidation of the type reported by Julia et al can tolerate a greater range of substituents than indicated by the prior art. More particularly, the present invention allows the preparation of the novel optically enriched epoxides of the formula I wherein R1, R2 and R3 are each independently selected from the H, R, R-CO- and RO-CO-, each R in independently is substantially a hydrocarbon group of up to 20 carbon atoms, and X is an alkyl or cycloalkyl group of up to 10 carbon atoms, with the proviso that -CO-X is not enolizable. The novel epoxides of the formula I constitute a further aspect of the invention. The nature of each R1, R2 and R3 is not critical, with the proviso that they do not interfere with the asymmetric epoxidation reaction. For example R1 is essentially a viewer for the reaction, whereby the non-enolizable nature of -CO-X is important. R1 can be, for example, a group of up to 10 carbon atoms. R2 and R3, and optionally also R1, may be H. R2 and R3 may be attached, for example together with - (Cr ^^ - Any other group other than H may comprise only C and H atoms, or may comprise 1 or more heteroatoms and / or substituents A preference for R1 is aryl or heteroaryl, optionally linked via a conjugation group to CR2, for example phenyl (or substituted phenyl) More preferably, X is t-butyl (for example when R1 is phenyl and R2 and R3 are each H), since substrates for epoxidation are readily available, or simply obtainable from readily available non-expensive starting materials such as pinacolone.Another non-enolizable group is provided when X is cyclopropyl. as alkyl it can be easily converted to alkoxy by the Baeyer-Villiger reaction.As indicated below, compounds in which X is t-butoxy are of particular interest.

The present invention provides, for example, an asymmetric route for ar, ß-unsaturated esters or other carboxylates such as amides, for the purpose of accessing, for example, the phenylisoserine component of the natural anticancer product toxol or intermediates for the antihypertensive drug dialtiazem. Obviously, a benefit of the methodology is that it can be obtained either the epoxide enantiomer with equal facility to use the appropriate catalyst, for example either the L- or the D-polyamino acid. Other catalysts can be used, as soon as they can be found effective, by trial and error. The catalyst can be a material obtainable by nucleophile-promoted oligomerization of an amino acid carboxy anhydride. An alternative catalyst is the immobilized catalyst system described by Itsonu et al, J. Org. Chem. (1990). The conditions reported by Julia et al, supra, for asymmetric epoxidation comprises a three phase system of poly-amino acid catalyst, an organic solvent such as N-hexane, and an aqueous phase containing a large excess of both oxidant ( hydrogen peroxide) and alkali (sodium hydroxide). For the economic use of the methodology for the manufacture of intermediates of a mass enantiomer, for, for example, pharmaceuticals, it may be desirable to reduce the need for any excess reagents. It has been found that, by the use of perborate solutions, the amount of alkali, for example, hydroxide, required in the reaction can be substantially decreased. As a result, apart from savings in reagents, substrates that are otherwise sensitive to the high alkali concentrations present may be used. Under the novel conditions, the oxidation system comprises the poly-amino acid catalyst, an organic solvent such as dichloromethane, and an aqueous phase containing perborate (sodium) and alkali, for example sodium hydroxide. In addition, some phase transfer catalyst such as Aliquota 336 is added. One finding is that only one equivalent of sodium hydroxide is required. These oxidation conditions can be applied to other heterogeneous oxidations. Scheme 1 below illustrates the reactions according to this invention, shows the useful modalities 1, 2 and 3, and an important use, illustrative of the products of this invention. All these modalities can be generalized within the scope of the invention. The following Examples illustrate the invention. As shown in Table 1, a variety of epoxyketones (R2 = R3 = H) have been prepared in good to excellent yield and excellent optical purity (Example A for comparison). All these epoxidations are carried out at room temperature in a three phase system with an organic solvent, a catalytic amount of poly-L-leucine synthesized according to Flisak et al, J. Org. Chem. (1993) 58: 6247, or poly-D-leucine synthesized in the same form from D-leucine, and with a large excess of oxidant. The preactivation of the catalyst, stirring the mixture for 6 hours before the addition of the α, β-unsaturated ketone, results in a shorter reaction time, for example from 1 to 3 days. Preferred solvents for those reactions are hydrocarbons such as hexane or chlorinated solvents such as dichloromethane. The optical purities (as given in Table 1) are determined by CLAP on a Chiralpac AD column, and the absolute configurations assigned as [2R, 3S] for those epoxies obtained from the use of poly-L-leucine. The catalyst can be recovered and reused.

Conditions (i) = poly-L-leucine / H202 / NaOH / CHCl2 (ii) = poly-D-leucine / H202 / Na0H / CHCl2 The results summarized in Table 1 show that the epoxidation reaction has a broad substrate specificity and is therefore not restricted to chalcone. The satisfactory enantioselectivities are obtained, including the case where the substrate has a second conjugated double bond (Example 4). Example A is a relatively long reaction, compared to Examples 1 and 2, due to the possibility of enolization. With reference to Scheme 1, as exemplification of the value of epoxyketones 1, a further aspect of the present invention is the use of (1S, 2R) -1,2-epoxy-4,4-dimethyl-1-phenyl-3-pentanone. 2 (synthon 3 is an alternative) in processes for the preparation of taxol side chain syntheses such as 4 (2R, 3S) -N-benzoyl-3-phenylisoserine syntheses, where the functionality of t-butyl ketone serves as a protected carboxylate. As summarized in Scheme 1, the conversion from 2 to 4 can be carried out by either the following sequences: (a) Baeyer-Villiger oxidation to produce t-butyl 2,3-epoxy-3-phenylpropanoate 5 , inverting the configuration at C-3 to give the cis-epoxide 6, opening the nucleophilic ring in the benzylic position with either ammonium or azide anion (followed by reduction to the amine), N-benzoylation and deesterification catalyzed by optional acid. In contrast to similar prior art processes for the corresponding n-alkyl ester (McChesney, Tetrahedron: Asymmetry (1994) 5: 1683; Jacobsen, J. Chem. (1992) 57: 4320), during the opening of the epoxide ring with ammonium the p-butylester provides effective protection against unwanted amidation in C-1, and allows a final deprotection of the carboxyl group C -1 to be carried out under mild non-hydrolytic conditions. (b) Similar to (a), but with the Baeyer-Villiger oxidation carried out in the penultimate stage. By this route, t-butyl ketone provides effective protection for the carboxyl group C-1 through most of the synthesis. Scheme 2 shows another use for a compound of the invention, ie in the synthesis of a precursor -hydroxyester for L-2-naphthylalanine.

Scheme 1 - •? II (2) 1. BCBÍA 2. XI? CHjClj f) (4) Scheme 2

Claims (31)

1. CLAIMS 1. A process for preparing an optically enriched chiral epoxide of the formula (I) characterized in that R1, R2 and R3 are each independently selected from H, R, R-CO- and R-0-CO-, each R independently is substantially a hydrocarbon group of up to 20 carbon atoms, and X is a alkyl or cycloalkyl group of up to 10 carbon atoms, with the proviso that -CO-X is not enolizable, which comprises the asymmetric epoxidation of a corresponding prochiral alkene of the formula II
2. R1R2OCRS-C0-X CU) by reaction with an oxidant in the presence of a chiral catalyst. 2. The process according to claim 1, characterized in that the catalyst is a heterogeneous chiral polymer.
3. 3. The process according to claim 1, characterized in that the catalyst is a metal-free synthetic polypeptide.
4. 4. The process according to claim 1, characterized in that the catalyst is obtainable by nucleophilic oligomerization of an amino acid carboxy anhydride.
5. 5. The process according to claim 4, characterized in that the anhydride has the partial formula
6. 6. The process according to claim 5, characterized in that the oligomerization is caused by humidity or an amine.
7. 7. The process according to any of the preceding claims, characterized in that it is carried out in the presence of alkali such as hydroxide. The process according to any of claims 2 to 6, characterized in that it is carried out in a mixture of three phases of the polymer or oligomer, an organic solvent, and an aqueous phase containing the oxidant and alkali, in the presence of a catalytic amount of a phase transfer catalyst such as Aliquota 336. 9. The process according to claim 7 or claim 8, characterized in that no more than one alkali equivalent is used. 10. The process according to any of the preceding claims, characterized in that the oxidant is a perborate. 11. The process according to any of the preceding claims, characterized in that R2 and R3 are each H. 12. The process according to claim 11, characterized in that R1 is H. 13. The process in accordance with any of the claims 1 to 11, characterized in that R1 is a group of up to 10 carbon atoms. 14. The process according to any of the preceding claims, characterized in that X is t-butyl. 15. The process in accordance with the claim 14, characterized for the preparation of (1S, 2R) -trans-1, 2-epoxy-4,4-dimethyl-1-phenyl-3-pentanone from (E) -4,4-dimethyl-1-phenylpenten -3 -one 16. An optically enriched chiral epoxide of the formula I according to claim 1, characterized in that R1 is aryl or heteroaryl, optionally linked via an epoxide group to CR2. 17. The epoxide according to claim 16, characterized in that R1 is optionally substituted phenyl. 1
8. 8. The epoxide according to claim 16, characterized in that R1 is phenyl. 1
9. 9. The epoxide according to any of claims 16 to 18, characterized in that X is t-butyl or cyclopropyl. 20. The epoxide according to claim 19, characterized in that X is t-butyl. 21. The epoxide according to any of claims 16 to 20, characterized in that it is in more than 80% enantiomeric excess. 22. The process for the preparation of an optically enriched epoxide ester, characterized in that it comprises converting X is an epoxide obtained by a process according to any of claims 1 to 15, or as claimed in any of claims 16 to 21, for OX, by the Baeyer-Villiger reaction. 23. The process in accordance with the claim 22, characterized in that OX is t-butoxy. 24. The use of (1S, 2R) -trans-1, 2-epoxy-4, 4-dimethyl-1-phenyl-3-pentanone for the preparation of syn-3-phenylisoserine or a derivative thereof represented by the formula enriched in the stereoisomer (2R, 3S), wherein R 'is H or acyl and R "is H or alkyl 25. The use according to claim 24, wherein R' is benzoyl. according to claim 24, comprising: (i) Baeyer-Villiger oxidation to produce (2R, 3S) -t-butyl 2,3-epoxy-3-phenylpropanoate, (ii) inversion of the C-3 configuration to give the corresponding cis-epoxide, (iii) opening of the nucleophilic ring in the benzylic position with either ammonium or azide anion (followed by reduction to the amine), and (iv) N-benzoylation and, optionally, catalysed deesterification by acid 27. The use according to claim 24, which comprises: (i) conversion to an intermediate of formula 7, and (ii) Baeyer-Villiger oxidation to give the product where R "is H or t -butyl and, optionally, acid catalyzed deesterification. 28. The process according to claim 14, characterized by the preparation of (1S, 2R) -trans-1, 2-epoxy-1- (4-methoxyphenyl) -4,4-dimethyl-3-pentanone from (E) -1- (4-methoxyphenyl) -4,4-dimethyl-l-penten-3-one. 29. The epoxide according to claim 17, characterized in that R1 is 4-methoxyphenyl. 30. The epoxide according to any of claims 16, 17, 18, 21 and 29, characterized in that X is ter-alkyl. 31. The use (1S, 2R) -trans-1, 2-epoxy-l- (4-methoxyphenyl) -4,4-dimethyl-3-pentanone for the preparation of diltiazem.