DE10134172A1 - New alpha-hydroxy-ketone derivatives, useful as intermediates for biologically active polyketides, terpenoids, epothilones and their derivatives - Google Patents

Abstract

alpha -Hydroxy-ketone (acyloin) compounds (I), in non-racemic, optically active or racemic form at the alpha -hydroxy-position, and their hydroxy-protected derivatives are new. Also new are several classes of new intermediates for and conversion products of (I). alpha -Hydroxy-ketone (acyloin) compounds of formula (I), in non-racemic, optically active or racemic form at the alpha -hydroxy-position, and their hydroxy-protected derivatives are new: R1 = H, alkyl, aryl, aralkyl (e.g. arylmethyl or arylethyl), vinyl, alkynyl (preferably propynyl), allyl (preferably 3,3-dialkylallyl; sic), cycloalkyl (preferably 3-7 membered), CHnFn-3, oxacycloalkyl (preferably 3-7 membered) or a combination of these; R2 = alkyl, aryl, alkaryl (e.g. arylmethyl or arylethyl), vinyl, alkynyl (preferably propynyl), allyl (preferably alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl or 3,3-dihaloallyl; sic), cycloalkyl (preferably 3-7 membered), CHnFn-3, oxacycloalkyl (preferably 3-7 membered) or a combination of these; and n = 0-3. Independent claims are included for: (1) new intermediates for and conversion products of (I), having formulae R1-C(Z)-CH(R2)-C(O)-R3 (V), Aux-N asterisk -C(O)-CHR'2-O-P' (VI), (VII), (X), (Xa), (XI), (XIa), (XII), (XIII), (XVa) and (XVb); (2) the preparation of the new compounds; and (3) the preparation of epothilone compounds of formula (XVI), by ring-closing lactonization, Reformatsky-type reactions and/or macro-aldolization of (XVa) or (XVb). Aux-N asterisk = N-O-alkyl (preferably N-OMe) or an Evans auxiliary of the oxazolidinone or imidazolidinone type; H, Me, Et or propyl (especially Me); R'2 = allyl derivative group of formula (a); B<1> - B<3> = single bond, triple bond, double bond (in E-, Z- or E/Z-mixture form), epoxide or cyclopropane ring (in E-, Z- or E/Z-mixture form), in particular B<1> being a Z-double bond or epoxide and B<1> and B<3> being single bonds; R4 = H, halo, alkyl, aryl, aralkyl (e.g. arylmethyl or arylethyl), vinyl, cycloalkyl (preferably 3-7 membered), CHnFn-3, oxacycloalkyl (preferably 3-7 membered) or a combination of these, especially H, Me, Et or Cl; n = 0-3; E = Me, CH2OH, CH2OP', CHO, COOR, COOP', CH2X, CON(R)2, CON(P')2, CON(OMe)Me or CN, especially CH2OH, CH2OP' or CHO; P' = protecting group; P'' = H or P'; X = H, OH, halo or other leaving group; R, R', R'' = as R4 but not halo; preferably R = H, Me or Et, R' = H and R'' = Me; Nu = R, OP', OR, N(P')2, dialkylamino, SP', alkylthio, SeP', alkylselenyl, CN, N3 or aryl, especially H or alkyl; Y = S, NH, NP', NR or O; R3 = alkyl, aryl, aralkyl (e.g. arylmethyl or arylmethyl), alkoxyalkyl or fluoroalkyl (preferably Me, Et or propyl); Z' = O, =N-Nu, =CH-heteroaryl, =CH-aryl or P(R3)3 (all in E-, Z- or E/Z-mixture form), especially (E)-(2-methylthiazol-4-yl)-CH= or (E)-(2-methyloxazol-4-yl)-CH=; X' = as X but not H; Y' = OH, OR, OP', NH2, N(R)2, N(P')2, SR or SH; Y'' = OH, OR, OP', NH2, N(R)2, N(P')2, SR, SH, Cl, Br or C(R')2-G; Z'' = O, OH, OP', NH, NH2, NR, N(R)2, NP', N(P')2, SR, SP' or R; G = E, CN, COR, dialkyl phosphonate, SO2R, SO2OR, CF3, CCl3 or NO2; in (VII), (X), (Xa), (XI), (XII), (XIII), (XVa), (XVb) and (XVI) aryl moieties are phenyl, naphthyl, benzyl or their derivatives; and heteroaryl moieties are 5- or 6-membered heteroaryl containing one or more O, S or N atoms, optionally substituted by 1-4 of alkyl, alkoxy and halo:

Description

The invention relates to racemic and in particular non-racemic acyloins, the Derivatives, processes for their preparation and their use for the production of Epothilones and their derivatives.

Acyloins or α-hydroxyketones (and aldehydes) are important functional units in many biologically active substances. They are also important intermediate stages for the Synthesis and as a small bifunctional unit meaning as a double link with further synthesis components, e.g. B. in heterocycle chemistry.

The same applies to derivatives of acyloins, especially those in which the hydroxyl group is esterified or otherwise protected or derivatized. Acyloine with unprotected Hydroxy groups are also known as free acyloins. The keto (or aldehyde) group can mainly by acetal formation, condensation, z. B. to imines etc., or alkenylation, z. B. can be derivatized by Wittig-type reactions.

All α-monosubstituted acyloins and their derivatives have in common that they are at the α- (OH) carbon, i.e. H. at the α-hydroxyposition have a chiral center which can easily racemize through the adjacent keto group. With many acyloin, especially simple with free acyloin (PG = H), it can also lead to an acyloin shift, a Exchange of keto and hydroxy groups via a dihydroxyalkene-like intermediate to lead. This is preferably done under base catalysis.

In the context of the present invention, asymmetrically substituted acyloins are those which carry different substituents R ¹ and R ² on the keto group and on the α-hydroxymethylene group, that is to say those which form an acyloin of a different constitution in the case of an acyloin shift. The names of the substituents always refer to the standard formula, not the shift version with the reversed keto / alcohol function, which is shown here only for demonstration purposes.

Acyloins are preferred by acyloin condensation from carboxylic acid derivatives or Aldehydes produced, a process which is particularly suitable for symmetrical acyloins is. Other processes use the oxidation of 1,2-diols and the reduction of 1,2- Dioxo compounds. The latter methods were also asymmetrical, too enzymatic reactions carried out (see e.g. Bioorg. Chemistry 21, 1993, 342; Bull. Chem. Soc. Jpn. 1994, 3314; J. Chem. Soc., Perkin Trans I 1991, 1329, ibid. 1996, 425; J. Chem. Soc., Chem. Commun. 1993; 341, J. Org. Chem. 51, 1986, 25-36; ibid. 1997, 1854). All of the above methods have in common that they are not or only bad for the targeted synthesis of asymmetric acyloins can be used because cross-couplings or regioselective redox reactions are often difficult to master or on a larger scale (Cofactors) are feasible.

Acyloins and their derivatives, in particular those with an allyl substituent as R ² - that is homoallylacyloins (homoallyl alcohols) - and with a methyl radical as preferred R ¹ , are also excellent building blocks for the synthesis of epothilones, the acyloine unit being primarily C15 and C16 (Epothilone numbering see below).

Epothilones are natural substances with an extraordinary biological effect, e.g. B. as Mitosis inhibitors, microtubule-modifying agents, cytotoxics or fungicides.

In particular, they have paclitaxel-like properties and outperform paclitaxel (Taxol®) in some tests. You are currently in clinical trials to treat cancer.

Epothilones, especially Epothilones B and D, have a C7-C18 (methyl) unit in the "North half", which corresponds structurally to a modified polyprenyl (polyisoprene) chain, and Z. B. according to German patent applications No. 197 13 970.1 and No. 100 51 136.8 can be represented; as well as a C1-C6 (methyl) unit in the "southern half", which is made of aldol type Reactions, e.g. B. according to German Offenlegungsschrift No. 197 01 758.4, (1998), can be represented.

The terms structural element, synthesis building block and building block are used in the context of present invention used synonymously. The numbering of epothilone building blocks follows that of the epothilon (see above). In particular, substituents and especially Methyl branches are in the naming of the building blocks as C (number) -C (number) range usually not mentioned separately, but are explicitly - but not necessarily - included locked in.

So far, the production of the structural element C7-C21 of the epothilones or of Subunits, especially C7-C15 / 16 and C11-C15 / 16 building blocks, usually Allyl compounds including prenyl derivatives, synthesized, the allyl compounds with difficult to access or in the wrong oxidation state C15-C16- Methyl building blocks were linked.

In processes for the production of the northern epothilone half, in which one for C15 and C16 the epothilone synthesis was in the correct oxidation state, especially according to the German one Patent application 100 51 136.8 usually produces racemates. So all point so far known methods of building the north half of Epothilon have the disadvantage that a asymmetric synthesis is difficult to carry out.

are α-hydroxy ketones with at least one chiral center at the α-hydroxy position important precursors of biologically active substances such as polyketides and terpenoids and in particular epothilones and their derivatives. On economic manufacturing process is therefore of great importance.

An optimal and economical, possibly enzyme-catalyzed production of other The α-hydroxy position of non-racemic acyloins should advantageously be a range of Fulfill conditions such as high enantioselectivity based on the α- Hydroxy position of the acyloin; high diastereoselectivity; a good space-time Yield (short reaction times, high conversions based on one enantiomer, high reactant and product concentrations); a high substrate width of the enzyme, a high chemical Yield of the desired product; small amounts of catalyst (in particular Amounts of enzyme); easy cleaning of the synthesis products; a good solubility of Educt and product under the reaction conditions; as well as an inexpensive synthesis, d. H. easy to prepare educts, easy handling of the educts, solvents, reagents and enzymes.

The object of the present invention is therefore to overcome the disadvantages of To overcome the prior art and in particular to provide a method that fulfills as many of the above conditions as possible.

In particular, it is an object of the present invention to provide an alternative and to provide an improved method with which preferably asymmetrically substituted Acyloins and acyloin derivatives, possibly with a high enantiomeric excess of α-hydroxy Position of the acyloins can be produced. It is also an object of the present Invention to provide compounds as building blocks in the synthesis of polyketides and terpenoids, in particular epothilones and / or their derivatives can and especially in the α-hydroxy position of the azeloin unit is not racemic are.

Further tasks result from the description below.

To solve the aforementioned problems are used in the independent claims defined characteristics.

Advantageous refinements are described in the subclaims.

The object of the invention is achieved in particular by compounds having the general formula I


are provided, whereby
R ^{1 is} selected from the group consisting of H; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially 3,3-dialkylallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered cycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of H, methyl, ethyl and propyl; and is particularly preferably methyl; and
R ^{2 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially alkyl allyl, 3,3-dialkylallyl, E- or Z-3-haloalkyl, 3,3-dihaloallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered oxacycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of propynyl, in particular alkylpropynyl; Allyl, in particular 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihalallyallyl, and particularly preferably an allyl derivative of type Y (attachment to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl.

In a preferred embodiment of the present invention, the compound of the invention at the α-hydroxy position of the general formula I not racemic or optically active. In this embodiment, the invention Compounds particularly suitable for use in the economic synthesis of Polyketides and terpenoids, especially of epothilones and their derivatives, because of this way a high enantioselectivity and diastereoselectivity is ensured, whereby in particular a clinical application of the end products is made possible.

At the α-hydroxy position of the general formula I racemic, as above However, described compounds are also the subject of the present invention.

The radical R ² in the general formula I is preferably selected from the group consisting of propynyl or propargyl and allyl radicals.

The radical R ² in the general formula I is particularly preferably an alkylpropinyl radical and the compound is racemic and / or non-racemic at the α-hydroxyl position of the general formula I.

If the radical R ² in the general formula I is an allyl radical, R ^{2 is} selected from the group consisting of 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl and 3,3-dihaloallyl.

A particularly preferred compound according to the invention has, as radical R ² in general formula I, an allyl derivative of type Y (linkage to formula I in X)


on, where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl.

For use as an epothilone building block, it is particularly advantageous if radical R ² or Y is selected from the group consisting of a neryl and a geranyl radical, in particular from the group consisting of one at the ω position to the alcohol, to the aldehyde or to the carboxylic acid oxidized and / or ω-1/2-hydrogenated neryl or geranyl derivative. Examples of the radical R ² can thus be selected from the group consisting of an ω-hydroxy and an ω-oxo (ω-1/2) dihydro-neryl radical.

Also of particular advantage with regard to a possible use of the Compounds according to the invention in the synthesis of the northern half of epothilone is when the absolute configuration at the α-hydroxyposition of general formula I of natural Configuration of epothilones at position C15 corresponds.

In a further possible embodiment of the present invention, the α- Hydroxy group of the general formula I protected by a protective group PG. In particular, the protective group PG is an acyl group. The is particularly preferred Protective group PG selected from the group consisting of an acetyl, propionyl, Butyroyl and benzoyl group.

An example of the compound according to the invention has the general formula III


on in the
R ² = propynyl and / or propynyl derivatives of the CH ₂ -C ~ CR type with R = alkyl, homoallyl, CH ₂ X;
R ^{3 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; alkoxyalkyl; fluoroalkyl; and is preferably selected from the group consisting of alkyl, benzyl and phenyl; and particularly preferably selected from the group consisting of methyl, ethyl and propyl; and
EWG is an electron-withdrawing functional group such as CO ₂ R, CO ₂ PG, CN, CO-R, alkylphosphonate, SO ₂ -R, SO ₂ OR, and preferably CO ₂ R, CO ₂ PG, and particularly preferably CO ₂ -t-Bu is.

The general formula IV has another example of the compounds according to the invention


on in the
R ² = propynyl and / or propynyl derivatives of the CH ₂ -C ~ CR type with R = alkyl, homoallyl, CH ₂ X; and
R ^{3 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; alkoxyalkyl; fluoroalkyl; and is preferably selected from the group consisting of alkyl, benzyl and phenyl; and particularly preferably selected from the group consisting of methyl, ethyl and propyl.

In a further aspect of the present invention there is provided a compound in which the α-hydroxy group of the general formula I


is protected by a non-racemic chiral acyl group, where
R ^{1 is} selected from the group consisting of H; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially 3,3-dialkylallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered cycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of H, methyl, ethyl and propyl; and is particularly preferably methyl; and
R ^{2 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially alkyl allyl, 3,3-dialkylallyl, E- or Z-3-haloalkyl, 3,3-dihaloallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered oxacycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of propynyl, in particular alkylpropynyl; Allyl, in particular 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihalallyallyl, and particularly preferably an allyl derivative of type Y (attachment to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl.

Such at the α-hydroxy position provided with non-racemic acyl groups Compounds are particularly suitable as building blocks for the synthesis of polyketides and Terpenoids, epothilones and / or their derivatives, since they separate the diastereomers Allow synthesis building blocks and consequently the production after the acyl group has been split off enantiomerically enriched acyloins or acyloin derivatives and other epothilone building blocks is guaranteed.

In particular, the α-hydroxy group of the general formula I is replaced by a non- racemic chiral acyl group selected from the group consisting of 2-alkoxy and 2- (N, N-Di-PG-amino) acyl groups protected. The α-hydroxy group is particularly preferred general formula I with optically active 2-alkoxymandelic acid or 2-alkoxy lactic acid and preferably esterified with 2-methoxymandelic acid as a non-racemic protective group.

In a further aspect of the present invention, a compound having the general formula VI


provided, where
Aux-N * is a NO-alkyl, preferably NO-methyl, and / or an Evans-type auxiliary of the oxazolidinone or imidazolidinone type;
R ^{2 is} an allyl derivative of type Y (linked to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl,
and preferably radical R ^{2 is} selected from the group consisting of a neryl and a geranyl radical, and particularly preferably radical R ^{2 is} selected from the group consisting of an oxidized at the ω position to alcohol, aldehyde or carboxylic acid and / or ω-1/2-hydrogenated neryl or geranyl derivative, and most preferably radical R ^{2 is} selected from the group consisting of an ω-hydroxy and ω-oxo (ω-1/2) dihydro-neryl ; and
PG 'is selected from the group consisting of H and protective groups which do not react in the usual enolization of the auxiliary intermediates, and is preferably selected from the group consisting of silyl, benzyl and oxymethyl derivatives.

With the above-mentioned inventive, with an Evans-type auxiliary provided acyloin or acyloin derivatives is also an enantiomerically enriched Synthesis of polyketides and terpenoids, epothilones and / or their derivatives possible.

The Evans-type auxiliary Aux-N * is preferably an optically active oxazolidinone or N-methylimidazolidinone with the general formula


in which
R at positions 4 and / or 5 of the oxazolidinone or N-methylimidazolidinone is selected from the group consisting of methyl, phenyl, isopropyl, benzyl, polymeric radicals and combinations thereof.

For example, the Evans-type auxiliary is derived from ephedrines.

In a further aspect of the present invention, a compound having the general formula V


provided, where
R ^{1 is} selected from the group consisting of H; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially 3,3-dialkylallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered cycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of H, methyl, ethyl and propyl; and is particularly preferably methyl; and
R ^{2 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially alkyl allyl, 3,3-dialkylallyl, E- or Z-3-haloalkyl, 3,3-dihaloallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered oxacycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of propynyl, in particular alkylpropynyl; Allyl, in particular 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihalallyallyl, and particularly preferably an allyl derivative of type Y (attachment to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl;
R ^{3 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; alkoxyalkyl; fluoroalkyl; and is preferably selected from the group consisting of alkyl, benzyl and phenyl; and particularly preferably selected from the group consisting of methyl, ethyl and propyl; and
Z is selected from the group consisting of = O, = N-Nu, = CH-hetaryl, = CH-aryl and = PR ₃ ; and preferably = CH-hetaryl; and is particularly preferably selected from the group consisting of (E) - (2-methylthiazol-4-yl) -CH = and (E) - (2-methyloxazol-4-yl) -CH =; where all groups Z can be in (E) form, (Z) form or as (E / Z) mixture.

Such a compound with the general formula V, especially if it is on the α- Hydroxy position of the general formula V is not racemic or optically active and / or Z is a carbonyl radical, represents a particularly preferred structural element for the epothilone Synthesis.

• a) Umsetzung von Verbindungen der allgemeinen Formel II
  
  
  wobei
  R¹ ausgewählt wird aus der Gruppe bestehend aus H; Alkyl; Aryl; Alkyl-Aryl wie CH₂-Aryl, C₂H₄-Aryl usw.; Vinyl; Alkinyl, insbesondere Propinyl; Allyl, insbesondere 3,3-Dialkylallyl; Cycloalkyl, insbesondere ein 3- bis 7gliedriges Cycloalkyl; CH_nF_3-n (n = 0-3); Oxacycloalkyl, insbesondere ein 3- bis 7gliedriges Cycloalkyl; Aux-N*, wobei Aux-N* ausgewählt wird aus der Gruppe bestehend aus N-O-Alkyl, vorzugsweise N-O-Methyl, und einem Evans-Typ-Auxiliar vom Oxazolidinon- oder Imidazolidinon-Typ, vorzugsweise einem optisch aktiven Oxazolidinon- oder N-Methylimidazolidinon mit der allgemeinen Formel
  
  
  wobei R an den Positionen 4 und/oder 5 des Oxazolidinons bzw. Imidazolidinons ausgewählt wird aus der Gruppe bestehend aus Methyl, Phenyl, Isopropyl, Benzyl, polymeren Resten und Kombinationen davon; und/oder Kombinationen davon; und vorzugsweise R¹ ausgewählt wird aus der Gruppe bestehend aus H, Methyl, Ethyl und Propyl; und besonders bevorzugt R¹ Methyl ist;
  R³ ausgewählt aus der Gruppe bestehend aus Alkyl; Aryl; Alkyl-Axyl wie CH₂-Aryl, C₂H₄- Aryl usw.; Alkoxyalkyl; Fluoroalkyl; und vorzugsweise ausgewählt wird aus der Gruppe bestehend aus Alkyl, Benzyl und Phenyl; und besonders bevorzugt ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl und Propyl; und
  EWG eine elektronenziehende funktionelle Gruppe wie CO₂R, CO₂PG, CN, CO-R, Alkylphosphonat, SO₂-R, SO₂OR, und vorzugsweise CO₂R, CO₂PG, und besonders bevorzugt CO₂-t-Bu ist;
  mit Resten R², ausgewählt aus der Gruppe bestehend aus Alkyl; Aryl; Alkyl-Aryl wie CH₂- Aryl, C₂H₄-Aryl usw.; Vinyl; Alkinyl, insbesondere Propinyl; Allyl, insbesondere Alkyl-allyl, 3,3-Dialkylallyl, E- oder Z-3-Halogenalkyl, 3,3-Dihalogenallyl; Cycloalkyl, insbesondere ein 3- bis 7gliedriges Cycloalkyl; CH_nF_3-n (n = 0-3); Oxacycloalkyl, insbesondere ein 3- bis 7gliedriges Oxacycloalkyl und/oder Kombinationen davon; und vorzugsweise ausgewählt wird aus der Gruppe bestehend aus Propinyl, insbesondere Alkylpropinyl; Allyl, insbesondere 3- Alkylallyl, 3,3-Dialkylallyl, E- oder Z-3-Halogenallyl, 3,3-Dihalogenallyl, und besonders bevorzugt mit einem Allylderivat vom Typ Y (Anknüpfung bei X)
  
  
  ist, wobei
  B¹ und/oder B² für eine Einfach- oder Dreifachbindung; eine Doppelbindung als E-(trans)- Form, Z-(cis)-Form oder E/Z-Gemisch; einen Epoxid- oder Cyclopropanring als E-(trans)- Form, Z-(cis)-Form oder E/Z-Gemisch und/oder Kombinationen davon steht; und vorzugsweise für Einfach- und Doppelbindungen steht; und besonders bevorzugt B¹ für eine Z-Doppelbindung oder ein Epoxid und B² für eine Einfachbindung steht;
  R⁴ H; Halogen wie F, Cl, Br oder I; Alkyl; Aryl; Alkyl-Aryl wie CH₂-Aryl, C₂H₄-Aryl usw.; Vinyl; Cycloalkyl, insbesondere ein 3- bis 7gliedriges Cycloalkyl; Oxacycloalkyl, insbesondere ein 3- bis 7gliedriges Oxacycloalkyl; und/oder Kombinationen davon ist; und vorzugsweise H, Methyl, Ethyl, CH_nF_3-n (n = 0-3), und/oder Halogen ist; und besonders bevorzugt H, Methyl, Ethyl und/oder Cl ist;
  E CH₃, CH₂OH, CH₂OPG, CH=O, CO₂R, CO₂PG, CH₂X, CONR₂, CON(PG)₂, CON(OMe)(Me) und/oder CN ist; und vorzugsweise CH₃, CH₂X, CO₂R und/oder CO₂PG ist; und besonders bevorzugt CH₂OH, CH₂OPG und/oder CH=O ist; und
  Nu R⁴, O-PG, OR, N(PG)₂, NAlkyl₂, SPG, S-Alkyl, SePG, Se-Alkyl, CN, N₃, Aryl, Heteroaryl ist; und vorzugsweise R⁴, OPG, O-Alkyl, N(PG)₂ und/oder N-Alkyl₂ ist; und besonders bevorzugt H und/oder Alkyl ist;
  zu Verbindungen der allgemeinen Formel III
  
  
  
• b) Umsetzung der Verbindung der allgemeinen Formel III zu Verbindungen der allgemeinen Formel IV
  
  
  beispielsweise durch Alkyldecarboxylierung oder Verseifen/Decarboxylierung von Verbindungen der allgemeinen Formel III mit EWG = CO₂R oder CO₂PG, vorzugsweise nach der dem Fachmann bekannten Krapcho-Methode, besonders bevorzugt ausgehend von III mit EWG = CO₂tBu in Gegenwart geeignet starker Säuren, vorzugsweise flüchtiger und/oder wasserfreier Säuren, besonders bevorzugt Trifluoressigsäure;
• c) Solvolyse der Verbindung der allgemeinen Formel IV zu freien α-Hydroxyketonen der allgemeinen Formel I
  
  
  in Gegenwart geeigneter Lösemittel und ggf. geeigneter Katalysatoren, und/oder
• d) Racematspaltende Veresterung von Verbindungen der allgemeinen Formel I.

Another object of the present invention provides a process for the preparation of the compounds according to the invention described above, which comprises at least one of the following steps:

• a) implementation of compounds of general formula II
  
  
  in which
  R ^{1 is} selected from the group consisting of H; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially 3,3-dialkylallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, especially a 3- to 7-membered cycloalkyl; Aux-N *, where Aux-N * is selected from the group consisting of NO-alkyl, preferably NO-methyl, and an Evans-type auxiliary of the oxazolidinone or imidazolidinone type, preferably an optically active oxazolidinone or N- Methylimidazolidinone with the general formula
  
  
  where R at positions 4 and / or 5 of the oxazolidinone or imidazolidinone is selected from the group consisting of methyl, phenyl, isopropyl, benzyl, polymeric radicals and combinations thereof; and / or combinations thereof; and preferably R ^{1 is} selected from the group consisting of H, methyl, ethyl and propyl; and particularly preferably R ^{1 is} methyl;
  R ^{3 is} selected from the group consisting of alkyl; aryl; Alkyl axyl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; alkoxyalkyl; fluoroalkyl; and is preferably selected from the group consisting of alkyl, benzyl and phenyl; and particularly preferably selected from the group consisting of methyl, ethyl and propyl; and
  EWG is an electron-withdrawing functional group such as CO ₂ R, CO ₂ PG, CN, CO-R, alkylphosphonate, SO ₂ -R, SO ₂ OR, and preferably CO ₂ R, CO ₂ PG, and particularly preferably CO ₂ -t-Bu is;
  with radicals R ² selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially alkyl allyl, 3,3-dialkylallyl, E- or Z-3-haloalkyl, 3,3-dihalogenallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered oxacycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of propynyl, in particular alkylpropynyl; Allyl, in particular 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihaloallyl, and particularly preferably with an allyl derivative of type Y (attachment to X)
  
  
  is where
  B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
  R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
  E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
  Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl;
  to compounds of the general formula III
  
  
  
• b) implementation of the compound of general formula III to compounds of general formula IV
  
  
  for example by alkyl decarboxylation or saponification / decarboxylation of compounds of the general formula III with EWG = CO ₂ R or CO ₂ PG, preferably by the Krapcho method known to the person skilled in the art, particularly preferably starting from III with EWG = CO ₂ tBu in the presence of suitably strong acids , preferably volatile and / or anhydrous acids, particularly preferably trifluoroacetic acid;
• c) Solvolysis of the compound of general formula IV to free α-hydroxy ketones of general formula I.
  
  
  in the presence of suitable solvents and, if appropriate, suitable catalysts, and / or
• d) Racemate-splitting esterification of compounds of the general formula I.

The process steps a) to d) described above can be carried out in any, the Expert more familiar and preferably in the order given above be performed. Furthermore, depending on the desired product, one or more of the Process steps are omitted.

The compounds of the general formula II with radicals R are converted, for example, by propinylations or allyllations which are familiar to the person skilled in the art, the radicals R ² preferably being H at their point of attachment; OH; or halogen or other usual leaving groups and their combinations; preferably Cl, Br, I, O-tosyl, methyl sulfonate, trifluoromethyl sulfonate, alkanoate and aryl carboxylates; and particularly preferably H, Cl, Br; are provided.

In particular, the solvolysis is carried out in step c) of the process according to the invention Hydrolysis with water and / or transesterification with alcohols.

The catalysts for the solvolysis in step c) are basic, acidic and / or Lewis acid catalysts conceivable. The catalysts are preferably selected are selected from the group consisting of alkali hydroxides, alkaline earth hydroxides, Alkali hydrogen carbonates, alkaline earth hydrogen carbonates, alkali carbonates, Alkaline earth carbonates, nitrogen bases, inorganic acids, organic acids, in particular aromatic sulfonic acids or polymer-bound acids, and Lewis acid catalysts such as lanthanide salts, titanium salts, in particular Titanium (IV) alkoxides.

Some Lewis acid catalysts can only according to their chemical properties can be used under anhydrous conditions.

The reaction temperature is in the range of -80 ° C to 150 ° C, depending on the reactivity and Solvent system, but preferably in the range of 0 ° C to 90 ° C, and especially preferably in the range from 15 ° C to 35 ° C.

Working up is usually carried out by shaking out with the usual organic ones Solvents, drying and optionally distillative, crystallizing and / or chromatographic purification.

It is further preferred that the solvolysis in step c) is carried out by the mild basic hydrolysis slightly basic catalysts, preferably in aqueous and / or alcoholic solutions, with higher alkali carbonates or dilute alkali hydroxides as catalyst, preferably being metered in during the reaction such that the pH is one Carbonate solution does not exceed. The reaction is preferably carried out in methanol or Ethanol with aqueous sodium or potassium carbonate solution.

In further embodiments described below, the invention Processes described by which by asymmetric synthesis or racemate resolution, but preferably by enzymatic and / or chemical-physical resolution non-racemic, asymmetrically substituted acyloins and acyloine esters and their derivatives can be prepared, preferably those derivatives which are used as epothilone Synthesis building blocks can serve, especially those that are in the German Patent application 100 51 136.8 are described, the disclosure of which is hereby expressly Reference is made.

Racemate cleavages have rarely been carried out on acyloin, almost only on symmetrical acyloin, without acyloin shift problem or with one poorer result in terms of enantiomeric purity and / or yield and / or Rotational value, and / or more complex than the method described below (see e.g. J. Chem. Soc. Chem. Commun. 1997, 1399; Tetrahedron: Asymmetry 10, 1996, 2207; ibid. 1997, 2773; Tetrahedron Lett. 1997, 6429). There are also few examples of Racemate resolution of homoallylic alcohols (e.g. tetrahedron: Asymmetry 10, 1999, 315). Also the C15 racemate cleavage of advanced epothilone north halves Thiazole methylidene side chain provided insufficient enantiomeric excesses (Tetrahedron Lett. 41, 2000, 1863-1866; see also Synthesis 1999, 1469). The especially for Epothilone building blocks important combination to homoallylacyloin (= allylic substituted Acyloine, R = allyl and derivatives, esp. Y) has so far not been successful in enzymatic Subject to resolution. In particular, substrates must be used for these racemate separations with protected and z. T. unprotected functional groups (z. B. 7-OH) implemented which allows further conversion to epothilones and epothilone derivatives.

As will be described in the following, within the scope of the present invention for the first time suitable conditions and especially suitable enzymes for these reactions made available. It was also found for the first time that certain genetically by Vitro evolution favored modified enzymes for the synthesis of these non-racemic Epothilon north half blocks can be used.

The following illustration schematically describes an example of the synthesis of racemic acyloin precursors and acyloins:

Surprisingly, it has been found that the use of certain non-racemic Acyloxy groups as protective groups for the α-hydroxy group of acyloin or acyloin Derivatives the diastereomer separation of acyloin precursors and / or protected acyloins allowed, and thus for example after hydrolysis or other reaction, the synthesis enantiomerically enriched acyloins or acyloin derivatives and, if necessary, more advanced ones Epothilone building blocks is possible. In particular, it was found that this is from the Most or all of the diastereomers are successful with the obtaining of an enantiomeric excess.

An idealized diasteromer separation is illustrated in the following illustration:

Thus, in a particularly preferred embodiment of the present invention, a process is provided in which the compounds of the general formula I which are non-racemic at the α-hydroxyposition are prepared by reacting compounds of the general formulas II, III and IV, the α- Hydroxy group is protected by a non-racemic chiral acyl group (R ³ = R *).

In particular, in this embodiment the α-hydroxy group can be optically more active 2-alkoxymandelic acid or 2-alkoxylactic acid and preferably with 2- Methoxymandelic acid are esterified.

Furthermore, it was found in the context of the present invention that the auxiliar-controlled synthesis of such acyloins with 2-oxy-substituted acetyl derivatives analogous to the Evans method.

The following illustration shows an "enantioselective" synthesis of acyloins (N-aux = chiral auxiliary of the Evans type, preferably oxazolidinone or in particular imidazolidinone derivatives):

Thus, in an alternative embodiment of the process according to the invention, compounds of the general formula I which are non-racemic at the α-hydroxy position are prepared via intermediates in the form of compounds of the general formula VI


and, if appropriate, subsequent purification by chromatography, PG 'being selected from the group consisting of H and protective groups which do not react in the usual enolization of the auxiliary-modified intermediates, and preferably being selected from the group consisting of silyl, benzyl and oxymethyl derivatives.

In this embodiment, the compounds having the general formula VI are in particular provided by reacting non-racemic 4- and / or 5-substituted N- [O-PG] acetyl-N-methylimidazolidinones, in which PG is a protective group, with α Hydroxyketone compounds, if appropriate in the presence of base, preferably lithium dialkylamides and / or alkali hexamethyldisilazides. The α-hydroxyketone compounds comprise the radical R ² , in particular the radical Y, particularly preferably neryl derivatives, and suitable leaving groups X.

The purification and optionally diastereomer separation is preferably carried out by liquid chromatographic methods on achiral solid phases such as silica gel.

The production of non-racemic at the α-hydroxyposition is particularly preferred Compounds of the general formula I by addition of organometallic compounds, preferably of alkyl lithium or alkyl magnesium compounds, particularly preferred of methyl or ethyl lithium or methyl or ethyl Grignard compounds Compounds of the general formula VI.

It has also surprisingly been found that racemic free acyloin under partial, preferably predominant and particularly preferably almost complete Racemate resolution can be esterified enzymatically to O-acyl acyloin.

The following illustration ideally illustrates an enzymatic esterification with resolution of racemate:

This takes place in a further alternative and particularly preferred embodiment of the method according to the invention the production of non-at the α-hydroxyposition racemic compounds of the general formula I or IV by racemate-cleaving enzymatic esterification of compounds of type I.

In particular, the esterification is carried out using an active ester, preferably isopropenyl and / or vinyl acetate.

The enzymes catalyzing the esterification are preferably selected from the Group consisting of lipases and esterases are particularly preferred lipases, for example lipases from Pseudomonas cepacia and / or Candida antarctica.

Alternatively, esterases from Pseudomonas fluorescens and / or Streptomyces used diastatochromogenic.

For example, a solution of the acyloin in a suitable organic solvent, preferably an alkane, particularly preferably toluene; with a lipase or esterase, also in immobilized or otherwise prepared form, preferably a lipase; and one Active ester, preferably isopropenyl or vinyl acetate, particularly preferably in light Excess; preferably between 10-70 ° C, particularly preferably at the enzymatic optimum (plus / minus 10 ° C), if necessary with agitation, preferably shear-free stirring or shaking, for Bring reaction until the desired implementation has occurred. The reaction is through Working up or preferably centrifugation ended, the solvent removed and by Vacuum evaporation removed. Esters and unreacted free acyloin can be distilled, be separated by crystallization or chromatography, preferably by chromatography solid phase (e.g. on silica gel or aluminum oxide).

Furthermore, it was surprisingly found in the context of the present invention that it alternatively with racemic O-acylated acyloin (PG = acyl, preferably acetyl, butyryl, Benzoyl) succeeds in non-resolving racemates by means of enzymatic hydrolysis. opposite racemic free acyloin and non-racemic O-acyl acyloin To achieve stereochemistry.

Such an enzymatic hydrolytic racemate resolution is ideally illustrated in the following illustration:

Thus, in another alternative and also particularly preferred Embodiment of the method according to the invention the production of at the α- Hydroxyposition non-racemic compounds of general formula I or IV by Racemate-splitting enzymatic hydrolysis of compounds of type IV takes place.

The enzyme which catalyzes the hydrolysis is preferably selected from the group consisting of lipases and esterases. For example, lipases from Pseudomonas cepacia and / or Candida antarctica can be used. Alternatively, esterases are made Pseudomonas fluorescens and / or Streptomyces diastatochromogenes advantageous. Especially recombinant pig liver esterase is preferably used as the enzyme.

For example, in this embodiment, an ester of the general formula IV in a buffer dissolved or suspended, preferably a phosphate or carbonate buffer; and the hydrolase, preferably a lipase or esterase, also in immobilized or otherwise prepared form, added. For larger batches, buffering can be preferred pH-controlled addition of base can be achieved. The pH value depends on the known or certain optimum and limit values of the enzyme, with a pH value between these values, which allows optimal reaction management, is ideal. The reaction takes place preferably between 10-70 ° C, particularly preferably at the enzymatic optimum (plus / minus 10 ° C) until the desired reaction has taken place, preferably with agitation, preferably by shear-free stirring or shaking. The reaction is with a conversion of 50% (related to racemate) carried out, possibly a little below or less often above if this is conducive to a higher optical purity of the target product (alcohol or ester). The Work-up is carried out by extraction with suitable non-water-miscible organic Solvents (esters, ethers, aromatics, also simple alkanes if product is soluble), preferred with ethyl acetate or toluene. In some cases, the extraction yield can be determined by the increase previous addition of small amounts of acetone or other solubilizers, or by centrifuging the enzyme beforehand. The processing and cleaning follows the usual processes also described above.

The enzyme-catalyzed racemate-resolving hydrolysis or Esterification preferably takes place in a temperature range from 10 ° C to 70 ° C. Lipase CAL-B in particular has a temperature optimum of 60 ° C and can do without can also be used at temperatures up to 70 ° C. Another possible one preferred temperature range for those suitable in the method according to the invention Temperatures is e.g. B. 20 ° C-45 ° C.

In all of the processes according to the invention described above, it is advantageous if, between the respective synthesis steps or before use as a synthesis building block, for example in epothilone synthesis, diastereomer separation of compounds of the general formulas I, II, III, IV and / or V, the α- Hydroxy group is protected by a non-racemic chiral acyl group (R ³ = R *) is carried out. The diastereomer separation can be carried out, for example, by crystallization, cocrystallization, distillation, sequential extraction, e.g. B. HSCCC (high speed counter current chromatography) and / or chromatographic separation, preferably by chromatographic separation, particularly preferably by liquid chromatographic methods on achiral solid phases such as silica gel.

In a further preferred embodiment, the compounds of the general formula IV become compounds of the general formula V


implemented
where Z is selected from the group consisting of = O, = N-Nu, = CH-hetaryl, = CH-aryl and = PR ₃ ; and preferably = CH-hetaryl; and is particularly preferably selected from the group consisting of (E) - (2-methylthiazol-4-yl) -CH = and (E) - (2-methyloxazol-4-yl) - CH =; where all groups Z can be in (E) form, (Z) form or as (E / Z) mixture.

The reaction is preferably carried out by Wittig type reactions known to those skilled in the art. The conversion to a compound having the general formula is particularly preferably carried out

In this way, particularly suitable building blocks for epothilone synthesis Provided.

All of the reactions described above can be carried out on separate diastereomers and / or on the mixture of diastereomers.

All of the synthesis building blocks and process steps described above can be found in the provision of compounds of the general formula I, preferably in non- racemic form at the α-hydroxy position.

In a further alternative embodiment of the method according to the invention the compounds of general formulas I, II, IV and / or V under anhydrous, strong basic conditions, preferably with the bases trialkylamine, DBU, DBN and / or polymeric strong bases racemized. In this way, a return to the Racemate resolution enables.

For this purpose, for example, the free or protected acyloin is used in an anhydrous one organic solvents, preferably an alkane, ether and / or aromatics, dissolved and with the Base offset. The temperature, preferably 0 ° C to 65 ° C, particularly preferably 25 ° C to 40 ° C, can be increased to the boiling point of the solvent for faster isomerization unless there are strong side reactions. After completing the Isomerization is filtered through silica gel or washed out with acid or with Scavenger resin stirred to remove the basic catalyst.

Another object of the present invention is the use of the compounds according to the invention as a building block, in particular as a C ₁₅ -C ₁₆ -containing building block for the production of epothilones and their derivatives.

Finally, another object of the present invention is the use of the The method according to the invention in the production of epothilones and their derivatives.

In the context of the present invention, the radicals in the general formulas given above comprise the following substituents:
R ¹ : H, alkyl, aryl, alkyl aryl (CH ₂ aryl, C ₂ H ₄ aryl etc.), vinyl, alkynyl, propargyl, allyl, 3,3-dialkylallyl, cycloalkyl (3-7-membered), CH _n F _3-n (n = 0-3), oxa-cycloalkyl (3-7-membered) and / or combinations thereof, preferably H, methyl, ethyl, propyl, particularly preferably methyl.
R ² : alkyl, aryl, alkyl aryl (CH ₂ aryl, C ₂ H ₄ aryl etc.), vinyl, alkynyl, propargyl, allyl, alkyl allyl, 3,3-dialkyl allyl, E- or Z-3 -Halogenalkyl, 3,3-dihalallyallyl, cycloalkyl (3-7-membered), CH _n F _3-n (n = 0-3), oxa-cycloalkyl (3-7-membered) and / or combinations thereof, preferably propargyl and alkylpropargyl, allyl and 3-alkylallyl and 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihaloallyl, particularly preferably type Y allyl derivatives (attachment to X)


in which
B ¹ , B ² : single or triple bond, double bond as E (trans) form, Z (cis) form or E / Z mixture; also epoxy or cyclopropane ring, as E- (trans) form, Z- (cis) form or E / Z mixture; preferably single and double bonds; particularly preferably with B ¹ as a Z double bond or epoxy and with B ² as a single bond; and / or combinations thereof;
R ⁴ : H, halogen (F, Cl, Br, I), alkyl, aryl, alkyl aryl (CH ₂ aryl, C ₂ H ₄ aryl etc.), vinyl, cycloalkyl (3-7-membered), oxa- cycloalkyl (3-7-membered) and / or combinations thereof, preferably H, methyl, ethyl, CH _n F _3-n (n = 0-3), halogen, particularly preferably H, methyl, ethyl, Cl; or combinations thereof;
E: CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me), CN, preferably CH ₃ , CH ₂ X, CO ₂ R, CO ₂ PG, particularly preferably CH ₂ OH, CH ₂ OPG, CH = O;
X: connecting point (as a formula part) or: H; OH; or halogen or other usual leaving groups and their combinations; preferably Cl, Br, I, O-tosyl, methyl sulfonate, trifluoromethyl sulfonate, alkanoate and aryl carboxylates; particularly preferably H, Cl, Br;
Nu: R ⁴ , O-PG, OR, N (PG) ₂ , NAkkyl ₂ , SPG, Salkyl, SePG, SeAlkyl, CN, N ₃ , aryl, heteroaryl, preferably R ⁴ , OPG, OAlkyl, N (PG) ₂ , NAlkyl ₂ , particularly preferably H, alkyl.
R ³ : alkyl, aryl, alkyl-aryl (CH ₂ aryl, C ₂ H ₄ aryl etc.), alkoxyalkyl, fluoroalkyl, preferably alkyl, benzyl, phenyl, particularly preferably methyl, ethyl, propyl.
R *: chiral non-racemic radicals, in particular those optically active carboxylic acids and derivatives (esters, halides, anhydrides) R * -CO-X, which are commercially available or are usually used for the formation of diastereomers, for. As mandelic acid, O-protected mandelic acid, lactic acid, O-protected lactic acid, N-protected amino acids, tartaric acid derivatives, camphoric acid etc., preferably ≙ chiral N-protected amino and O-protected hydroxycarboxylic acids, particularly preferably O-alkylmandelic acid, very particularly with R * = CH (OMe) Ph.
Z: = O, = N-Nu, = CH-hetaryl, = CH-aryl, = PR ₃ ; where all the aforementioned double-bonded groups Z are in (E) form, (Z) form or as (E / Z) mixture, preferably = CH-hetaryl; particularly preferred = O, (E) - (2-methylthiazol-4-yl) -CH =, (E) - (2-methyloxazol-4-yl) -CH =.
EEC: usual electron-withdrawing functional groups such as CO ₂ R, CO ₂ PG, CN, CO-R, alkylphosphonate, SO ₂ -R, SO ₂ OR, preferably CO ₂ R, CO ₂ PG, particularly preferably CO ₂ -t-Bu.
N-Aux *: usual Evans-type auxiliaries of oxazolidinone (Evans et al. Pure & Appl. Chem. 1981, 53, 1109-1127) or imidazolidinone-type (Close, WJ, J. Org. Chem., 1950, 15 , 1131), derived from non-racemic amino alcohols or diamines, commercially available or accessible from amino acids, ephedrines etc. by methods known from the literature, particularly preferably non-racemic imidazolidinones derived from ephedrine.
Alkyl denotes hydrocarbon radicals, also branched isomers, with preferably 1 to 8 carbon atoms.
Aryl denotes phenyl, naphthyl, benzyl and their derivatives with up to five alkyl, alkoxy or halogen substituents, but preferably those with up to three substituents, particularly preferably with up to one substituent; corresponding phenyl and benzyl derivatives are preferred; and combinations thereof.
Hetaryl or heteroaryl denotes five- and six-membered heteroaromatics with one or more O, S, and N atoms; and their derivatives with up to four alkyl, alkoxy or halogen substituents, but preferably those with up to two substituents, particularly preferably with up to one substituent; corresponding oxazole, thiazole and pyrimidine derivatives are preferred; particularly preferably alkylthiazole and oxazole derivatives; and combinations thereof.
PG denotes usual protecting groups for the given linking atom or the given functional group, e.g. B. according to the book GREENE / WUTS 1991 (Protective Groups in Organic Synthesis, ISBN 0-471-62301-6), such as allyl, t-butyl, methyl, benzyl, silyl, acyl or activated methylene derivatives such as methoxymethyl, alkoxyalkyl or 2-oxacycloalkyl-protecting groups; preferred - predominantly for alcohol and amine functions - trimethylsilyl, triethylsilyl, dimethyl-tert-butylsilyl, acetyl, propionyl, benzoyl, tetrahydropyranyl.
PG 'are groups which do not react with the usual enolization of the auxiliary-modified intermediates (e.g. with LDA), such as silyl, benzyl or oxymethyl derivatives according to the above literature.
Act are common activators that are suitable for enzymatic acyl transfer. These are usually anhydrides or active esters such as alkenyl esters (Act = O-vinyl, O-isopropenyl etc.), trifluoroethyl esters, oxime esters or thioesters, preferably alkenyl esters, particularly preferably O-vinyl and O-isopropenyl.

Synthesis building blocks produced according to the invention have the general structural formula I, II, III, IV and V, preferably the formula I, IV or V with R ¹ = Me and R ² = Y, and can be in racemic or non-racemic form or as individual diastereomers or as a mixture of diastereomers. The structural elements with the general formulas I and V can preferably be used as products or as intermediates in the synthesis of active substances. In addition, the structural elements according to the invention with the general formulas I to V can be used for the synthesis of polyketide and terpenoid natural products or derivatives of polyketide and terpenoid natural products, preferably, like V, for the synthesis of macrocyclic active compounds such as epothilones and their Derivatives including stereoisomers and / or homologues, Nor compounds, and / or as wholly or partially inverted elements, in which they are preferably as C15 / C16 building blocks, as C12-C16 building blocks, as C11-C16 and C7-C16 or particularly preferably can serve as C7-C16 (Me) building blocks of the ring, which can additionally carry pre-formed elements or the entire side chain at C15 or C16 of the ring. The synthesis building blocks are preferably enriched in an enantiomeric and / or diastereomeric form, particularly preferably the absolute configuration corresponding to the natural epothilones. Furthermore, compounds according to the invention having the general structural formula I, IV and V are provided, in which the functional groups have been completely or partially protected by PG.

The compounds according to the invention with the general formulas I, II, III, IV and V are according to the invention at C15 (or at shift acyloin at C16) in optically active form u. a. provided by asymmetric synthesis linked to alkoxyacetyl compounds Evan-type auxiliaries, through formation of diastereomers and subsequent separation with optical active acids and their derivatives, and by racemate resolution by means of enzymatic Hydrolysis or esterification; preferably by one of the latter two methods, particularly preferably by enzymatic processes.

The compounds according to the invention with the general formulas I, II, III, IV and V usually have at least one substituent in the lowest C position that is suitable to enable links to other epothilone building blocks, for. B. at C7 especially with C1-C6 components, such as B. in the German patent application DE 197 01 758.4 are listed.

The embodiment of the invention is not limited to the above preferred embodiments. Rather, a large number of variants are conceivable, which ones of the solutions shown, even with fundamentally different types Makes use of.

The present invention will hereinafter be described by way of further examples illustrated, which are by no means to be interpreted as restrictive.

Examples

The stereocenters drawn in formulas make no statement regarding the absolute Configuration or optical purity justified, it is only in these cases non-racemic (optically active) products.

The abbreviations according to Table 1 are also used in the examples: Table 1 Ac: Acetyl
AYS: Lipase from Candida rugosa
BSDR: Bacillus stearothermophilus diacetyl reductase
CAA / CAL-A: Lipase type A from Candida antartica
CAB / CAL-B: Lipase type B from Candida antartica
CD: cyclodextrin
CPGC: Chiral phase gas chromatography
DMF: N, N dimethylformamide
E: Enantiomeric ratio according to Chen, CS; Fujimoto, Y .; Girdaukas, G .; Sih, CJ, J. Am. Chem. Soc. 1982, 104, 7294-7299.
ee: enantiomeric excess
LDH: lactate dehydrogenase
MJ: Lipase from Mucor javanicus
MPA: methoxyphenylacetic acid
NAD (H): (Reduced) nicotinamide adenine dinucleotide
NADP (H) (reduced) nicotinamide adenine dinucleotide phosphate
nd: not determined
NMR: Nuclear magnetic resonance spectroscopy
O-PG: O-protecting group
PPL: Porcine pancreas lipase
PS: Lipase from Pseudomonas cepacia
pTsOH: para-toluenesulfonic acid
TBDMS: see TBS
TBS (O): tert-butyldimethylsilyl (ether)
t-Bu: tert-butyl
TMS: tetramethylsilane

Part A Synthesis of racemic O-acyl acyloin and their precursors tert-butyl-2-acetoxy-2-acetyl-4-hexenoate

3.24 g (15.0 mmol) of tert-butyl-2-acetoxyacetoacetate are added to a suspension of 660 mg (16.5 mmol) of sodium hydride in 30 ml of DMF at 0 ° C. After the evolution of gas had ended, 2.00 g (15.0 mmol) of 1-bromo-2-butyne were added at 0.degree. The orange solution was stirred for 40 minutes and then warmed to room temperature in 15 minutes. After the addition of 120 ml of diethyl ether, the mixture was washed several times with 35 ml of water and finally with conc. Saline. The organic phase was dried with Na ₂ SO ₄ , filtered and freed from the solvent in vacuo.
Yield: 3.83 g (14.3 mmol, 95%)
R _f value: approx.0.57 with ethyl acetate / hexane = 1: 4.

3-acetoxy-5-heptyne-one 2-

1.61 g (6.00 mmol) of tert-butyl-2-acetoxy-2-acetyl-4-hexenoate, 114 mg (0.60 mmol) of para-toluenesulfonic acid monohydrate and 20 ml of benzene were stirred at 78 ° C. for 2 h. After the end of the reaction (end of gas evolution, discoloration), the crude product was poured onto silica gel with ethyl acetate / hexane = 1: 4 eluted. The fraction with the desired product is evaporated in vacuo.
Yield: 922 mg (5.48 mmol, 91%).

tert-butyl-2-acetoxy-2-acetyl-4-hexenoate

630 mg (2.3 mmol) of tert-butyl-2-acetoxy-2-acetyl-4-hexenoate are added to a suspension of 120 mg of Lindlar catalyst in 50 ml of ethyl acetate and evacuated twice and placed under a slightly positive pressure under a hydrogen atmosphere. After stirring for 24 h, the mixture is filtered through Celite® with ethyl acetate, washed with saturated sodium bicarbonate solution, dried with Na ₂ SO ₄ , filtered and the solvent is removed in vacuo.
Yield: 628 mg (2.32 mmol, 99%).

3-acetoxy-5-hepten-2-on

433 mg (1.60 mmol) of tert-butyl 2-acetoxy-2-acetyl-4-hexenoate, 30 mg (0.16 mmol) of para-toluenesulfonic acid monohydrate and 6 ml of benzene were stirred at 78 ° C. for 4 h. After the end of the reaction (end of gas evolution, discoloration), the crude product was poured onto silica gel and eluted with ethyl acetate / hexane 1: 4. The fraction with the desired product is evaporated in vacuo.
Yield: 205 mg (1.20 mmol, 75%)
R _f value: approx.0.50 with ethyl acetate / hexane = 1: 4.

3-acetoxy-6-methyl-heptan-2-one

300 mg (1.63 mmol) of 3-acetoxy-5-hepten-2-one and 60 mg of 5% palladium on carbon were stirred at room temperature in dry ethanol. After evacuation and gassing with hydrogen three times, the gas is still 25 min. slowly passed through the suspension. After filtering through Celite® and drying over Na ₂ SO ₄ , the mixture is filtered and the solvent is removed in vacuo.
Yield: 302 mg (1.62 mmol, 99%).

part B Diastereoselective syntheses and diastereomer separations of acyloin derivatives and preparation of non-acemic acyloins, acyloin derivatives, and Epothilonnordhälftebausteine (4S, 5R, 2'-not-rac) -1,5-dimethyl-4-phenyl-3- (2'-benzyloxy-5 ', 9'-dimethyldeca-4' (Z), 8' dienoyl) imidazolidin-2-on

To a solution of diisopropylamine (2.65 ml, 1.90 g, 18.8 mmol) in THF (25 ml) is added an n-butyllithium solution (1.88 ml, 10 M in hexane, 18 , 78 mmol) was added dropwise. The LDA solution thus obtained slowly became a solution of (4S, 5R) -1,5-dimethyl-4-phenyl-3- (benzyloxyacetyl) imidazolidin-2-one (5.30 g, 15.7 mmol) in THF (25 ml). After stirring at -78 ° C for 1 hour, neryl bromide (3.40 g, 15.7 mmol) was added dropwise. After stirring for three hours at -78 ° C, the cooling bath was removed and stirred for 15 minutes at ambient temperature. After quenching with a saturated NH ₄ Cl solution (25 ml), the organic solvent was removed in vacuo and the remaining aqueous phase was washed with demi. Diluted water (25 ml). It was extracted three times with 75 ml Et ₂ O and the combined organic phases were dried over Na ₂ SO ₄ . The desiccant was then filtered off and the solvent was removed in vacuo.

The product was purified by chromatography on silica gel (column dimension: 30 × 3 cm, EtOAc / petroleum ether = 1: 2).
Yield: 3.64 g (7.67 mmol, 49%).

Non-racemic 2-benzyloxy-N-methoxy-N, 5,9-trimethyldeca-4 (Z), 8-dienoylamide

Trimethylaluminum solution (4.50 ml, 2 M in toluene, 9.00 mmol) became a suspension of N, O-dimethylhydroxylamine hydrochloride (878 mg, 9.00 mmol) in CH ₂ Cl ₂ (12 ml ) slowly added dropwise. The mixture was stirred at ambient temperature for 15 minutes and then cooled to -10 ° C. Now a solution of (4S, 5R, 2'-non-rac) -1,5-dimethyl-4-phenyl-3- (2'-benzyloxy-5 ', 9'-dimethyldeca-4' (Z), 8'-dienoyl) imidazolidin-2-one (see above, 1.42 g, 3.00 mmol) in CH ₂ Cl ₂ (12 ml) was slowly added dropwise. It was stirred for one hour at -10 ° C, two hours at 0 ° C and 30 minutes at ambient temperature. The reaction mixture was finally poured into a mixture of 0.5 N HCl (100 ml) and CH ₂ Cl ₂ (50 ml) and shaken intensively for 5 minutes. The phases were separated and the aqueous phase extracted twice with CH ₂ Cl ₂ (2 × 25 ml). The combined organic phases were washed with 0.5 N HCl (60 ml) and 1 M phosphate buffer (60 ml, pH = 7.0) and then dried over Na ₂ SO ₄ . The desiccant was then filtered off and the solvent was removed in vacuo.

The product was purified by chromatography on silica gel (column dimension: 30 × 3 cm, EtOAc / petroleum ether = 1: 2).
Yield: 779 mg (2.25 mmol, 75%).

Non-racemic 3-benzyloxy-6,10-dimethylundeca-5 (Z), 9-dien-2-one

Methyl lithium lithium bromide complex (1.87 ml, 1.5 M in THF, 2.80 mmol) was converted at -78 ° C. to a solution of non-racemic 2-benzyloxy-N-methoxy-N, 5.9- trimethyldeca- 4 (Z), 8-dienoylamide (see above, 345 mg, 1.00 mmol) in CH ₂ Cl ₂ (15 ml) was added dropwise. The mixture was stirred at -78 ° C. for 40 minutes, then the reaction mixture was passed through a stainless steel cannula into a mixture of saturated NH ₄ Cl solution (20 ml), 14 ml hexane and 7 ml CH ₂ Cl, which was cooled to 0 ° C. and intensely stirred ₂ pumped. After thawing to ambient temperature, the mixture was diluted with saturated NaCl solution (50 ml) and with a 3: 1 hexane / CH ₂ Cl ₂ mixture (50 ml). It was shaken again intensively and after phase separation, the aqueous phase was extracted again with CH ₂ Cl ₂ (30 ml). The combined organic phases were washed with saturated NaCl solution (150 ml) and dried over Na ₂ SO ₄ . The desiccant was then filtered off and the solvent was removed in vacuo. The product could be obtained in high purity.
Yield: 308 mg (1.03 mmol, almost quantitative)
[α] 25 | D (c = 1, CHCl ₃ ) = -18.0 °.

11- (tert-butyl-dimethyl-silanyloxy) -3-hydroxy-6,10-dimethyl-undec-5-en-2-one

400 µl of saturated potassium carbonate solution are added to 1.94 g (5.05 mmol) of 3-acetoxy-11- (tert-butyl-dimethylsilyloxy) -6,10-dimethyl-5-undecen-2-one in 20.0 ml of methanol , After the reaction has ended (precise TLC control, for example about 10 minutes at room temperature), 30 ml of NaCl solution are added and the mixture is extracted five times with 30 ml of diethyl ether. The combined organic phases are washed again with NaCl solution and dried over sodium sulfate, the solvent is then removed in vacuo, and the residue is chromatographed on silica gel.
Yield: 1.68 g (4.92 mmol, 97%)
R _f value: 0.42
C ₁₉ H ₃₈ O ₃ Si (342.59)

(R) -methoxy-phenyl-acetic acid [(1R) -1-acetyl-9- (tert-butyl-dimethyl-silanyloxy) -4.8- dimethyl-non-3-enyl] ester and (R) -methoxy-phenyl-acetic acid [(1S) -1-acetyl-9- (tert-butyl-dimethyl-silanyloxy) -4.8- dimethyl-non-3-enyl] ester

To 50 mg (0.146 mmol) 11- (tert-butyl-dimethyl-silanyloxy) -3-hydroxy-6,10-dimethyl-undec-5-en-2-one, 27 mg (0.161 mmol) (R) -1 -Methoxy-phenyl-acetic acid and 4 mg (0.029 mmol) of 4,4'-dimethylaminopyridine (DMAP) in 1.0 ml of CH ₂ Cl ₂ , 56 mg (0.292 mmol) of the coupling reagent EDCI are added and the mixture is stirred at room temperature for 18 h. After adding 5 ml of diethyl ether, 2 ml of NaCl solution are extracted twice with 2 ml of water, the organic phase is dried over Na ₂ SO ₄ and the solvent is distilled off in vacuo. The O-methylmandelate (102 mg) contains two diastereomers, which can be separated by chromatography, on silica gel with a column of 1.0 × 20.0 cm, diethyl ether / petroleum ether = 2: 9.
Overall yield: 53 mg (0.108 mmol, 74%)
C ₂₈ H ₄₆ O ₅ Si (490.75) Fraction I 18 mg (0.037 mmol, 25%)
R _f value 0.31 (diethyl ether / petroleum ether = 1: 4)
Rotation value = -19.1 ° Fraction II Yield: 23 mg (0.047 mmol, 32%)
R _f value approx. 0.22 (diethyl ether / petroleum ether = 1: 4)
Rotation value = -23.9 °
C ₂₈ H ₄₆ O ₅ Si (490.75)

Optically active 11- (tert-butyl-dimethyl-silanyloxy) -3-hydroxy-6,10-dimethyl-undec-5- en-2-on

Mild basic hydrolysis (see below) of one of the diastereomeric methoxy-phenyl-acetic acid [(1- acetyl-9- (tert-butyl-dimethyl-silanyloxy) -4,8-dimethyl-non-3-enyl] ester non-racemic product.

(R) -methoxy-phenyl-acetic acid 9- (tert-butyl-dimethyl-silanyloxy) -4,8-dimethyl-1- [1- methyl-2- (2-methyl-thiazol-4-yl) -vinyl] -non-3-enyl ester

A solution of 1022 mg (2.92 mmol) of 2-methyl-4- (methyl-tributylphosphonium bromide) - 1,3-thiazole in 19.0 ml abs. THF was cooled to -65 ° C and 1.56 ml (3.12 mmol) one 2.0 M sodium hexamethyldisilazide solution in THF was slowly added dropwise. To for 10 minutes stirring a solution of 1194 mg (2.43 mmol) (R) -methoxy-phenylacetic acid (3S) -1-acetyl-9- (tert-butyl-dimethyl-silanyloxy) -4,8-dimethyl-non-3-enyl ester in 8.0 ml abs. THF slowly added dropwise.

After stirring for 60 minutes at -65 ° C, 45 ml of saturated NH ₄ Cl solution were added. The phases were separated and the aqueous phase extracted five times with 25 ml of diethyl ether. The organic phases were combined and washed three times with 30 ml of demineralized water and once with 50 ml of saturated NaCl solution. Finally, it was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The remaining brown oil was purified by means of flash chromatography on silica gel (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 5).
Yield: 1.3 g (2.3 mmol, approx. 95%)
R _f value: 0.37 (ethyl acetate / petroleum ether = 1: 5).

(R) -methoxy-phenyl-acetic acid (R) -9- (tert-butyl-dimethyl-silanyloxy) -4,8-dimethyl-1- [1- methyl-2- (2-methyl-thiazol-4-yl) -vinyl] -non-3-enyl ester

A solution of 1018 mg (2.91 mmol) of 2-methyl-4- (methyl-tributylphosphonium bromide) - 1,3-thiazole in 19.0 ml abs. THF was cooled to -65 ° C and 1.39 ml (2.79 mmol) one 2.0 M sodium hexamethyldisilazide solution in THF were slowly added dropwise. To for 10 minutes stirring a solution of 1190 mg (2.42 mmol) (R) -methoxy-phenylacetic acid (3R) -1-acetyl-9- (tert-butyl-dimethyl-silanyloxy) -4,8-dimethyl-non-3-enyl ester in 8.0 ml abs. THF slowly added dropwise.

After stirring for 60 minutes at -65 ° C, 45 ml of saturated NH ₄ Cl solution were added. The phases were separated and the aqueous phase extracted five times with 25 ml of diethyl ether. The organic phases were combined and washed three times with 30 ml of demineralized water and once with 50 ml of saturated NaCl solution. Finally, it was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The remaining brown oil was purified by means of flash chromatography on silica gel (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 5).
Yield: 1.282 mg (2.19 mmol, 90%)
R _f value: 0.37 (ethyl acetate / petroleum ether = 1: 5)
C ₃₃ H ₅₁ NO ₄ SSi: (585.91).

Part C. Hydrolysis of O-acyl acyloin

The enzymes described below are used below:
Lipases: Candida antarctica (Novo lipase B-Chirazyme L2, CAL-B), Candida antarctica (Novo, lipase A, CAL-A), Candida rugosa (Amano AY, CRL), Aspergillus niger (Amano, ANL), Pseudomonas cepacia ( Amano PS, PCL-PS), Pseudomonas cepacia (Amano AK, PCL-AK), Pseudomonas sp. (Chirazyme L6, PSL). AYS = Candida rugosa, CAA = Candida antartica A, CAB = Candida antartica B, MJ = Mucor javanicus, PS = Pseudomonas cepacia, PPL = porcine pancreas lipase.
Pig liver esterase, pig liver esterase (PLE, Sigma).
Production of recombinant esterases from Pseudomonas fluorescens (PFE, PFE-II), Streptomyces diastatochromogenes (SDE) by expression in E. coli according to literature (Krebsfänger, N .; Zocher, F .; Altenbuchner, J .; Bornscheuer, UT Enzyme Microb. Technol 1998, 21, 641-646. Khalameyzer, V .; Bornscheuer, UT Biotechnol. Lett. 1999, 21, 101-104. Khalameyzer, V .; Fischer, I .; Bornscheuer, UT; Altenbuchner, J. Appl. Environm Microbiol. 1999, 65, 477-482).
Recombinant pig liver esterase (rPLE) by expression in the yeast Pichia pastoris. (Musidlowska, A .; Lange, S .; Bornscheuer, UT Angew. Chem. Int. Ed. Engl. 2001, in print. Lange, S .; Musidlowska, A .; Schmidt-Dannert, C .; Schmitt, J. ; Bornscheuer, UT Chem. Bio. Chem. 2001, in press).

General instruction I for the (racemic) saponification of O-acyl acyloin

The ester is dissolved in methanol (e.g. 0.05-1 M, usually about 0.13 M) and then slowly with an aqueous base, preferably - and if not specifically mentioned - in saturated aqueous potassium carbonate solution added (80 µl per mmol ester). After completing Reaction (e.g. 30 min.) Is sat. NaCl solution (approx. 1.5 × the methanol volume) and five times the amount of ether. The organic phase is thoroughly with again Washed NaCl solution, dried with sodium sulfate, filtered, and in vacuo from the solvent freed. Further cleaning can e.g. B. by chromatography on silica gel.

General regulation II for the enzymatic resolution of O-acyl acyloin (small amounts)

In a suitable vessel (here e.g. an Eppendorf® 1.5 ml vessel), one after the other is loaded with lipase or esterase (e.g. about 20 mg), 0.7 ml phosphate buffer (0.1 M, pH 7, 0) and the acyloin ester (e.g. 5 µl). The mixture is shaken vigorously and shaken normally (vortex, 300 strokes / minute) at 0-60 ° C depending on the enzyme, usually at room temperature. The reaction is terminated by adding acetone. The course is usually checked by a titrator or a polarimeter, or over time, usually taking about 30 minutes. Ethyl acetate (0.4 ml) is added, shaken and centrifuged (at 8000 g for 5 min.). The top organic layer is removed and the rest extracted again. Extraction is more difficult to achieve without centrifugation. After drying the combined organic phases over Na ₂ SO ₄ , centrifugation can be carried out again (e.g. at 8000 g for 5 min).

The following Table 2 describes examples of reactions according to general regulation II with substrate IV R ¹ , R ³ = Me (ee values according to GC, 99+ = 99-100%, ¹ The ee values of the substrates are calculated values, alcohol / Esters 1 and 2 denote the other enantiomer). Table 2

General regulation III for the enzymatic resolution of O-acyl acyloin

The ester was dissolved in 0.1 M phosphate buffer pH 7.0 (concentration approx. 0.07 M) lipase added (e.g. up to 25% by weight of the acyloin ester). During the reaction up to Completeness shaken (DC and GC control). Acetone was added (1/2 of Buffer vol.) And extracted five times with ethyl acetate (1.5 × buffer vol.). The organic phases are washed twice with NaCl solution, dried with sodium sulfate and in vacuo freed from the solvent. Alcohol and ester are separated by chromatography (e.g. on Silica gel with ethyl acetate / petroleum ether = 1: 6).

General regulation IV for the enzymatic resolution of O-acyl acyloin Small approaches

10 mg hydrolase (lipase or esterase) in 1 ml Sodium phosphate buffer (pH 7.5, 50 mM) shaken in 2 ml reaction vessels at 37 ° C (e.g. with Thermoshaker - Eppendorf, Hamburg, Germany). Then 200 ul substrate solution added (10 mg / ml in toluene). After 20 h, the reaction is carried out by centrifuging off the Enzyme stopped, the toluene layer separated and analyzed (e.g. by GC, polarimetry).

Larger approaches

These are carried out similarly, but in 10 ml of phosphate buffer with 200 mg of hydrolase and 0.44 mmol (about 100 mg) of acyloin ester in 3 ml of toluene. At the end of the reaction, 10 ml of toluene are added, the enzyme is removed by centrifugation and the organic layer is separated off. The aqueous phase is extracted twice more with 5 ml of toluene, the combined organic phases are dried (Na ₂ SO ₄ ) and the solvent is removed in vacuo. Acyloin and the unreacted ester are separated by chromatography (e.g. on silica gel with petroleum ether: ether, 4: 1). Enantiomeric excesses can best be analyzed using chiral phase gas chromatography (CP-GC), chemical identity using NMR spectroscopy.

General regulation V for enzyme-catalyzed transesterification in organic solvents Enzymatic esterification of free acyloins

A solution of 0.44 mmol of the acyloin in 3 ml of toluene, activated molecular sieve (3 Å), 200 mg lipase or esterase and vinyl acetate (1.2 equivalents) are used at 37 ° C Bring reaction until the desired reaction has taken place (shaking if necessary). The reaction is ended by centrifugation, the solvent is removed and by Vacuum evaporation removed. Esters and unreacted free acyloin can be separated by chromatography (e.g. on silica gel with petroleum ether: ether, 4: 1). Enantiomeric excesses can best be determined using chiral phase GC, chemical identity be analyzed by means of NMR spectroscopy.

Instead of the vinyl acetate, other active esters can also be used. Table 3 Racemate resolution of acyloin acetate UWE1b according to regulation IV (small)

Table 4 Racemate resolution of acyloin acetate UWE3a according to regulation IV (small)

Racemic free acyloins (R, S) 3-hydroxy-5-hepten-2-one

According to general instructions I 48 mg (0.26 mmol) 3-acetoxy-5-hepten-2-one 20 min. hydrolyzed, the solution becoming cloudy and then yellowish. Chromatography (diethyl ether / petroleum ether = 1: 4) gives:
Yield: 28 mg (0.20 mmol, 77%)
R _f value: approx. 0.46 with ethyl acetate / hexane = 1: 4

(R, S) 3-hydroxy-nonan-2-one

According to general instructions I, 60 mg (0.30 mmol) of 3-acetoxy-nonan-2-one are hydrolyzed for 20 min, the solution becoming cloudy and then yellowish. Chromatography gives:
Yield: 42 mg (0.27 mmol, 88%)
R _f value: approx. 0.63 with ethyl acetate / hexane = 1: 4.

(R, S) 3-hydroxy-6-methyl-heptan-2-one

According to general instructions I 47 mg (0.25 mmol) 3-acetoxy-6-methyl-heptan-2-one are 5 min. hydrolyzed, the solution becoming cloudy and then yellowish.
Yield: 32 mg (0.22 mmol, 88%).

(R, S) 3-hydroxy-5 (Z) -hepten-2-one

According to general instructions I, 43 mg (0.25 mmol) of 3-acetoxy-5 (Z) -hepten-2-one are hydrolyzed for 5 minutes, the solution becoming cloudy and then yellowish.
Yield: 31 mg (0.24 mmol, 96%).

(R, S) (E) 3-hydroxy-6,10-dimethyl-5,9-undecen-2-one

According to general instructions I, 63 mg (0.25 mmol) of (E) 3-acetoxy-6,10-dimethyl-5,9-undecen-2-one are hydrolyzed for 6 min, the solution becoming cloudy and then yellowish.
Yield: 47 mg (0.22 mmol, 89%)
R _f value: approx. 0.35 with ethyl acetate / hexane = 1: 4.

(R, S) (Z) 3-hydroxy-6,10-dimethyl-5,9-undecen-2-one

According to general instructions I, 63 mg (0.25 mmol) of (Z) 3-acetoxy-6,10-dimethyl-5,9-undecen-2-one are hydrolyzed for 6 min, the solution becoming cloudy and then yellowish.
Yield: 47 mg (0.22 mmol, 89%) of a yellow oil
R _f value: 0.42 with ethyl acetate / hexane = 1: 4.

Optically active non-racemic alcohols and esters

The respective starting material is not additionally mentioned in the title. Optically active 3-hydroxy-heptan-2-one

According to general instruction III, 100 mg (0.58 mmol) of 3-acetoxy-heptan-2-one are reacted with 6 mg of Candida antartica B lipase in 10 ml of buffer and terminated after 3.75 h. After chromatography:
Yield:
Alcohol: 20 mg (0.15 mmol, 26%)
Ester: 35 mg (0.20 mmol, 35%)
R _f value:
Alcohol: approx. 0.33 with ethyl acetate / hexane = 1: 4
Ester: approx. 0.48 with ethyl acetate / hexane = 1: 4
[α] 25 | D (approximate values):
Alcohol: + 69.9 ° (c = 0.410; CHCl ₃ ; ee = 82%)
Ester: + 9.6 ° (c = 1.805; CHCl ₃ ; ee = 78%)

Optically active 3-hydroxy-nonan-2-one

According to general instructions III, 16 mg (0.58 mmol) of 3-acetoxy-nonan-2-one are reacted with 7 mg of Candida antartica B lipase in 10 ml of buffer and terminated after 4.5 hours. After chromatography:
Yield:
Alcohol: 10 mg (0.063 mmol, 11%)
Ester: 46 mg (0.23 mmol, 40%)
R _f value:
Alcohol: approx.0.44 with ethyl acetate / hexane = 1: 4
Ester: approx. 0.61 with ethyl acetate / hexane = 1: 4
[α] 25 | D:
Ester: + 6.3 ° (c = 1.615; CHCl ₃ ).

Optically active 3-hydroxy-5 (Z) -hepten-2-one

According to general instruction III, 32 mg (0.19 mmol) of 3-acetoxy-5 (Z) -hepten-2-one are reacted with 20 mg of Amano PS lipase in 5 ml of buffer and terminated after 40 min. The following products are obtained after chromatography:
R _f value:
Alcohol: approx. 0.30 with ethyl acetate / hexane = 1: 4
Ester: approx. 0.50 with ethyl acetate / hexane = 1: 4.

Optically active 3-hydroxy-6-methyl-5-hepten-2-one

According to general instruction III, 200 mg (1.09 mmol) of 3-acetoxy-6-methyl-5-hepten-2-one are reacted with 63 mg of Amano PS lipase in 15 ml of buffer and terminated after 6 hours. The following products are obtained after chromatography:
Yield:
Alcohol: 71 mg (0.50 mmol, 46%) of a clear colorless oil
Ester: 103 mg (0.56 mmol, 52%) of a clear colorless oil
R _f value:
Alcohol: approx. 0.22 with ethyl acetate / hexane = 1: 4
Ester: approx. 0.50 with ethyl acetate / hexane = 1: 4
[α] 25 | D:
Alcohol: + 77.3 ° (c = 0.979; CHCl ₃ )
Ester: -15.5 ° (c = 2.030; CHCl ₃ ).

Optically active 3-hydroxy-4-phenylbutan-2-one

According to general instructions III, 150 mg (0.73 mmol) of 3-acetoxy-4-phenylbutan-2-one are reacted with 38 mg of Amano PS lipase in 15 ml of buffer and terminated after 3 hours. The following products are obtained after chromatography:
Yield:
Alcohol: 51 mg (0.31 mmol, 43%) of a clear colorless oil
Ester: 76 mg (0.37 mmol, 50%) of a clear colorless oil.
[α] 25 | D:
Alcohol: + 64.1 ° (c = 0.820; CHCl ₃ ; ee = 89%)
Ester: -3.0 ° (c = 2.325; CHCl ₃ ; ee = 85%)

Optically active 3-hydroxy-6,10-dimethylundeca-5 (Z), 9-dien-2-one

According to general instruction III, 200 mg (0.79 mmol) of 3-acetoxy-6,10-dimethylundeca-5 (Z), 9-dien-2-one are reacted with 63 mg of Amano PS lipase in 15 ml of buffer and after 6 h completed. The following products are obtained after chromatography:
Yield:
Alcohol: 70 mg (0.33 mmol, 42%) of a clear colorless oil
Ester: 107 mg (0.42 mmol, 54%) of a clear colorless oil.
R _f value:
Alcohol: approx. 0.38 with ethyl acetate / hexane = 1: 4
Ester: approx. 0.52 with ethyl acetate / hexane = 1: 4
[α] 25 | D:
Alcohol: + 63.7 ° (c = 2.115; CHCl ₃ ; ee = 95%)
Ester: -19.7 ° (c = 1.560; CHCl ₃ ; ee = 97%).

Optically active (Z) -3-acetoxy-6,10-dimethyl-5,9-undecadien-2-one and (Z) -3-hydroxy- 6,10-dimethyl-5,9-undecadien-2-one

Hydrolysis (larger approach) with PCL according to general Regulation IV gives optically active (Z) -3-acetoxy-6,10-dimethyl-5,9-undecadien-2-one (40% Yield,> 99% ee) and (Z) -3-hydroxy-6,10-dimethyl-5,9-undecadien-2-one (43% yield, 92% ee), E >> 100.

Optically active (E) -3-acetoxy-6,10-dimethyl-5,9-undecadien-2-one and (E) -3-hydroxy- 6,10-dimethyl-5,9-undecadien-2-one

Hydrolysis (larger approach) with PCL according to general Regulation IV gives optically active (E) -3-acetoxy-6,10-dimethyl-5,9-undecadien-2-one (40% Yield, 95% ee) and (E) -3-hydroxy-6,10-dimethyl-5,9-undecadien-2-one (32% yield, > 99% ee), E >> 100.

Optically active (Z) -3-hydroxy-6,10-dimethyl-5,9-undecadien-2-one and (Z) -3-acetoxy- 6,10-dimethyl-5,9-undecadien-2-one

Acylation with PCL according to general regulation V gives optically active (Z) -3-hydroxy-6,10-dimethyl-5,9-undecadien-2-one (40% yield, 95% ee) and (Z) -3-acetoxy-6,10-dimethyl-5,9-undecadien-2-one (32% yield,> 99% ee), E >> 100.

Optically active (E) -3-acetoxy-6,10-dimethyl-5-en-11-hydroxy-undecan-2-one and (E) -3- Hydroxy-6,10-dimethyl-5-en-11-hydroxy-undecan-2-one

Hydrolysis (0.94 mmol) with PCL according to general regulation IV, optically active (E) -3-acetoxy-6,10-dimethyl-5-en-11- hydroxy-undecan-2-one (28% yield, 92% ee) and alcohol (E) -3-hydroxy-6,10-dimethyl- 5-en-11-hydroxy-undecan-2-one (28% yield,> 99% ee), E >> 100.

Optically active (E) -3-acetoxy-6,10-dimethyl-5-en-11-O-TBDMS-undecan-2-one and (E) - 3-hydroxy-6,10-dimethyl-5-en-11-O-TBDMS-undecan-2-one

Hydrolysis (1.25 mmol) with PCL (Chirazyme L6) according to general regulation IV gives optically active (E) -3-acetoxy- 6,10-dimethyl-5-en-11-O-TBDMS-undecan-2-one (48% y, 46% ee) and alcohol 3-hydroxy- 6,10-dimethyl-5-en-11-O-TBDMS-undecan-2-one (42% yield,> 99% ee), E >> 100. A further improvement of the optical yields of (E) -3-acetoxy-6,10-dimethyl-5-en-11-O- TBDMS-undecan-2-one was eliminated by a second kinetic resolution with PCL (Amano PS) reached. Yield 35% (E) -3-acetoxy-6,10-dimethyl-5-en-11-O-TBDMS- undecan-2-one with> 98% ee.

Claims (51)

1. α-hydroxketone compound, particularly suitable as a building block for the synthesis of polyketides and terpenoids, epothilones and / or their derivatives, with the general formula I


in which
R ^{1 is} selected from the group consisting of H; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially 3,3-dialkylallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered cycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of H, methyl, ethyl and propyl; and is particularly preferably methyl; and
R ^{2 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloalkyl, 3,3-dihaloallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered oxacycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of propynyl, in particular alkylpropynyl; and allyl, in particular 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihalogenallyl, and particularly preferably an allyl derivative of type Y (attachment to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl,
characterized in that the compound at the α-hydroxy position of the general formula I is not racemic or optically active. 2. α-hydroxketone compound, particularly suitable as a building block for the synthesis of polyketides and terpenoids, epothilones and / or their derivatives, with the general formula I


in which
R ^{1 is} selected from the group consisting of H; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially 3,3-dialkylallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered cycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of H, methyl, ethyl and propyl; and is particularly preferably methyl; and
R ^{2 is} selected from the group consisting of propynyl, in particular alkylpropynyl; and allyl, in particular alkylallyl, 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihaloallyl, and particularly preferably an allyl derivative of type Y (attachment to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl,
characterized in that the compound at the α-hydroxy position of the general formula I is racemic. 3. A compound according to claim 1 or 2, characterized in that the radical R is an alkylpropinyl radical. 4. Connection according to one of the preceding claims, characterized in that the radical R is selected from the group consisting of 3- Alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl and 3,3-dihaloallyl. 5. Compound according to one of the preceding claims, characterized in that the radical R is an allyl derivative of the type Y (linkage with X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl. 6. Connection according to one of the preceding claims, characterized in that the radical R is selected from the group consisting of a neryl and a geranyl residue. 7. A compound according to any one of the preceding claims, characterized in that the radical R ^{2 is} selected from the group consisting of a neryl oxidized at the ω position to the alcohol, to the aldehyde or to the carboxylic acid and / or ω-1/2-hydrogenated - or geranyl derivative. 8. Compound according to one of the preceding claims, characterized in that the radical R ^{2 is} selected from the group consisting of an ω-hydroxy and ω-oxo (ω-1/2) dihydro-neryl radical. 9. Connection according to one of the preceding claims, characterized in that the absolute configuration at the α-hydroxy position of the general formula I of the natural configuration of epothilones at position C15 equivalent. 10. Connection according to one of the preceding claims, characterized in that the α-hydroxy group of the general formula I by a Protection group PG is protected. 11. A compound according to claim 10, characterized in that the protective group PG is an acyl group. 12. A compound according to claim 10 or 1 l, characterized in that the protective group PG is selected from the group consisting of an acetyl, propionyl, butyroyl and benzoyl group. 13. A compound according to any one of the preceding claims, characterized in that the compound has the general formula III


has in which
R ² = propynyl and / or propynyl derivatives of the CH ₂ -C ~ CR type with R = alkyl, homoallyl, CH ₂ X;
R ^{3 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; alkoxyalkyl; fluoroalkyl; and is preferably selected from the group consisting of alkyl, benzyl and phenyl; and particularly preferably selected from the group consisting of methyl, ethyl and propyl; and
EWG is an electron-withdrawing functional group such as CO ₂ R, CO ₂ PG, CN, CO-R, alkylphosphonate, SO ₂ -R, SO ₂ OR, and preferably CO ₂ R, CO ₂ PG, and particularly preferably CO ₂ -t-Bu is. 14. A compound according to any one of claims 1 to 12, characterized in that the compound has the general formula IV


has in which
R ² = propynyl and / or propynyl derivatives of the CH ₂ -C ~ CR type with R = alkyl, homoallyl, CH ₂ X; and
R ^{3 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; alkoxyalkyl; fluoroalkyl; and is preferably selected from the group consisting of alkyl, benzyl and phenyl; and is particularly preferably selected from the group consisting of methyl, ethyl and propyl. 15. Compound, particularly suitable as a building block for the synthesis of polyketides and terpenoids, epothilones and / or their derivatives, characterized in that the α-hydroxy group of the general formula I


is protected by a non-racemic chiral acyl group, where
R ^{1 is} selected from the group consisting of H; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially 3,3-dialkylallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered cycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of H, methyl, ethyl and propyl; and is particularly preferably methyl; and
R ^{2 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially alkyl allyl, 3,3-dialkylallyl, E- or Z-3-haloalkyl, 3,3-dihaloallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered oxacycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of propynyl, in particular alkylpropynyl; Allyl, in particular 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihalallyallyl, and particularly preferably an allyl derivative of type Y (attachment to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl. 16. A compound according to claim 15, characterized in that the α-hydroxy group of the general formula I by a non-racemic chiral acyl group selected from the group consisting of 2-alkoxy and 2- (N, N-Di-PG-amino) acyl groups, where PG is a protecting group. 17. A compound according to claim 15 or 16, characterized in that the α-hydroxy group of the general formula I with optical active 2-alkoxymandelic acid or 2-alkoxy lactic acid and preferably with 2- Methoxymandelic acid is esterified. 18. Compound, particularly suitable as a building block for the synthesis of polyketides and terpenoids, epothilones and / or their derivatives,
characterized in that the compound is a compound of the general formula VI


is where
Aux-N * is a NO-alkyl, preferably NO-methyl, and / or an Evans-type auxiliary of the oxazolidinone or imidazolidinone type;
R ^{2 is} an allyl derivative of type Y (linked to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl,
and preferably radical R ^{2 is} selected from the group consisting of a neryl and a geranyl radical, and particularly preferably radical R ^{2 is} selected from the group consisting of an oxidized at the ω position to alcohol, aldehyde or carboxylic acid and / or ω-1/2-hydrogenated neryl or geranyl derivative, and most preferably radical R ^{2 is} selected from the group consisting of an ω-hydroxy and ω-oxo (ω-1/2) dihydro-neryl radical ; and
PG 'is selected from the group consisting of H and protective groups which do not react in the usual enolization of the auxiliary intermediates, and is preferably selected from the group consisting of silyl, benzyl and oxymethyl derivatives. 19. A compound according to claim 18, characterized in that the Evans-type auxiliary Aux-N * is an optically active oxazolidinone or N-methylimidazolidinone with the general formula


is where
R at positions 4 and / or 5 of the oxazolidinone or N-methylimidazolidinone is selected from the group consisting of methyl, phenyl, isopropyl, benzyl, polymeric radicals and combinations thereof. 20. A compound according to claim 18 or 19, characterized in that the Evans-type auxiliary is derived from ephedrines. 21. Compound, particularly suitable as a building block for the synthesis of polyketides and terpenoids, epothilones and / or their derivatives, with the general formula V


in which
R ^{1 is} selected from the group consisting of H; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially 3,3-dialkylallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered cycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of H, methyl, ethyl and propyl; and is particularly preferably methyl; and
R ^{2 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially alkyl allyl, 3,3-dialkylallyl, E- or Z-3-haloalkyl, 3,3-dihaloallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered oxacycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of propynyl, in particular alkylpropynyl; Allyl, in particular 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihalallyallyl, and particularly preferably an allyl derivative of type Y (attachment to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl;
R ^{3 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; alkoxyalkyl; fluoroalkyl; and is preferably selected from the group consisting of alkyl, benzyl and phenyl; and particularly preferably selected from the group consisting of methyl, ethyl and propyl; and
Z is selected from the group consisting of = O, = N-Nu, = CH-hetaryl, = CH-aryl and = PR ₃ ; and preferably = CH-hetaryl; and is particularly preferably selected from the group consisting of (E) - (2-methylthiazol-4-yl) -CH = and (E) - (2-methyloxazol-4-yl) -CH =; where all groups Z can be in (E) -form, (Z) -form or as (E / Z) mixture, in particular the compound at the α-hydroxyl position of the general formula V is not racemic or optically active. 22. A method for producing compounds according to one of the preceding claims, comprising at least one of the following steps: a) implementation of compounds of general formula II


in which
R ^{1 is} selected from the group consisting of H; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially 3,3-dialkylallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, especially a 3- to 7-membered cycloalkyl; Aux-N *, where Aux-N * is selected from the group consisting of NO-alkyl, preferably NO-methyl, and an Evans-type auxiliary of the oxazolidinone or imidazolidinone type, preferably an optically active oxazolidinone or N- Methylimidazolidinone with the general formula


where R at positions 4 and / or 5 of the oxazolidinone or imidazolidinone is selected from the group consisting of methyl, phenyl, isopropyl, benzyl, polymeric radicals and combinations thereof; and / or combinations thereof; and preferably R ^{1 is} selected from the group consisting of H, methyl, ethyl and propyl; and particularly preferably R ^{1 is} methyl;
R ^{3 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; alkoxyalkyl; fluoroalkyl; and is preferably selected from the group consisting of alkyl, benzyl and phenyl; and particularly preferably selected from the group consisting of methyl, ethyl and propyl; and
EWG is an electron-withdrawing functional group such as CO ₂ R, CO ₂ PG, CN, CO-R, alkylphosphonate, SO ₂ -R, SO ₂ OR, and preferably CO ₂ R, CO ₂ PG, and particularly preferably CO ₂ -t-Bu is;
with radicals R ² selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially alkyl allyl, 3,3-dialkylallyl, E- or Z-3-haloalkyl, 3,3-dihalogenallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered oxacycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of propynyl, in particular alkylpropynyl; Allyl, in particular 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihaloallyl, and particularly preferably with an allyl derivative of type Y (attachment to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl;
to compounds of the general formula III


b) implementation of the compounds of general formula III to compounds of general formula IV


for example by alkyl decarboxylation or saponification / decarboxylation of compounds of the general formula III with EWG = CO ₂ R or CO ₂ PG, preferably according to the Krapcho method, particularly preferably starting from III with EWG = CO ₂ tBu in the presence of suitably strong acids, preferably more volatile and / or anhydrous acids, particularly preferably trifluoroacetic acid; c) Solvolysis of the compounds of general formula IV to free α-hydroxy ketones of general formula I.


in the presence of suitable solvents and, if appropriate, suitable catalysts; and or d) Racemate-splitting esterification of compounds of the general formula I. 23. The method according to claim 22, characterized in that the solvolysis in step c) by hydrolysis with water and / or transesterification with alcohols. 24. The method according to claim 22 or 23, characterized in that the solvolysis in step c) in the presence of basic, acidic and / or Lewis acid catalysts. 25. The method according to claim 24, characterized in that the catalysts are selected from the group consisting of alkali hydroxides, alkaline earth hydroxides, alkali hydrogen carbonates, Alkaline earth bicarbonates, alkali carbonates, alkaline earth carbonates, nitrogen bases, inorganic acids, organic acids, especially aromatic sulfonic acids or polymer-bound acids, and Lewis acid catalysts such as lanthanide salts, Titanium salts, especially titanium (IV) alkoxides. 26. The method according to any one of claims 22 to 25, characterized in that the reaction temperature is in the range from -80 ° C to 150 ° C, preferably in the range from 0 ° C to 90 ° C, and particularly preferably in the range from 15 ° C up to 35 ° C. 27. The method according to any one of claims 22 to 26, characterized in that the solvolysis in step c) by the mild basic hydrolysis with slightly basic catalysts, preferably in aqueous and / or alcoholic Solutions with higher alkali carbonates or dilute alkali hydroxides as catalyst takes place, preferably being metered in during the reaction such that the pH does not exceed that of a carbonate solution. 28. The method according to any one of claims 22 to 27, characterized in that the preparation of non-racemic compounds of the general formula I at the α-hydroxyposition is carried out by reacting compounds of the general formulas II, III and IV, their α-hydroxy group is protected by a non-racemic chiral acyl group (R ³ = R *). 29. The method according to claim 28, characterized in that the α-hydroxy group with optically active 2-alkoxymandelic acid or 2-alkoxy lactic acid is esterified and preferably with 2- Methoxymandelic acid is esterified. 30. A process for the preparation of compounds according to any one of claims 1 to 21, characterized in that the preparation of non-racemic compounds of the general formula I at the α-hydroxy position via intermediates in the form of compounds of the general formula VI


and optionally subsequent purification by chromatography, wherein Aux-N * is selected from the group consisting of NO-alkyl, preferably NO-methyl, and an Evans-type auxiliary of the oxazolidinone or imidazolidinone type, preferably an optically active oxazolidinone - or N-methylimidazolidinone with the general formula


where R at positions 4 and / or 5 of the oxazolidinone or imidazolidinone is selected from the group consisting of methyl, phenyl, isopropyl, benzyl, polymeric radicals and combinations thereof; and / or combinations thereof; and preferably R ^{1 is} selected from the group consisting of H, methyl, ethyl and propyl; and particularly preferably R ^{1 is} methyl;
R ^{2 is} selected from the group consisting of alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Alkynyl, especially propynyl; Allyl, especially alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloalkyl, 3,3-dihaloallyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; CH _n F _3-n (n = 0-3); Oxacycloalkyl, in particular a 3- to 7-membered oxacycloalkyl and / or combinations thereof; and is preferably selected from the group consisting of propynyl, in particular alkylpropynyl; and allyl, in particular 3-alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl, 3,3-dihalogenallyl, and particularly preferably an allyl derivative of type Y (attachment to X)


is where
B ¹ and / or B ² for a single or triple bond; a double bond as E- (trans) form, Z- (cis) form or E / Z mixture; an epoxy or cyclopropane ring is in the E- (trans) form, Z- (cis) -form or E / Z mixture and / or combinations thereof; and preferably stands for single and double bonds; and particularly preferably B ^{1 is} a Z double bond or an epoxy and B ^{2 is} a single bond;
R ⁴ H; Halogen such as F, Cl, Br or I; alkyl; aryl; Alkyl aryl such as CH ₂ aryl, C ₂ H ₄ aryl, etc .; Vinyl; Cycloalkyl, especially a 3- to 7-membered cycloalkyl; Oxacycloalkyl, especially a 3- to 7-membered oxacycloalkyl; and / or combinations thereof; and preferably is H, methyl, ethyl, CH _n F _3-n (n = 0-3), and / or halogen; and is particularly preferably H, methyl, ethyl and / or Cl;
E is CH ₃ , CH ₂ OH, CH ₂ OPG, CH = O, CO ₂ R, CO ₂ PG, CH ₂ X, CONR ₂ , CON (PG) ₂ , CON (OMe) (Me) and / or CN; and is preferably CH ₃ , CH ₂ X, CO ₂ R and / or CO ₂ PG; and particularly preferably CH ₂ OH, CH ₂ OPG and / or CH = O; and
Nu is R ⁴ , O-PG, OR, N (PG) ₂ , NAkyl ₂ , SPG, S-alkyl, SePG, Se-alkyl, CN, N ₃ , aryl, heteroaryl; and preferably R ^{4 is} OPG, O-alkyl, N (PG) ₂ and / or N-alkyl ₂ ; and is particularly preferably H and / or alkyl; and
PG 'is selected from the group consisting of H and protective groups which do not react when the auxiliary intermediates are customarily enolized, and is preferably selected from the group consisting of silyl, benzyl and oxymethyl derivatives; and in particular the compounds having the general formula VI have been prepared by reacting non-racemic 4- and / or 5-substituted N- [O-PG] acetyl-N-methylimidazolidinones, in which PG is a protective group, with α- Hydroxyketone compounds comprising the radical R ₂ , in particular the radical Y, particularly preferably neryl derivatives, and suitable leaving groups, if appropriate in the presence of base, preferably lithium dialkylamides and / or alkali hexamethyl disilazides. 31. The method according to claim 30, characterized in that the production of non-at the α-hydroxy position racemic compounds of general formula I by addition of Organometallic compounds, preferably of alkyl lithium or Alkyl magnesium compounds, particularly preferably of methyl or ethyl lithium or Methyl or ethyl Grignard compounds on compounds of the general formula VI he follows. 32. The method according to any one of claims 22 to 27, characterized in that the production of non-at the α-hydroxy position racemic compounds of the general formula I or IV by racemate-cleaving enzymatic esterification of compounds of type I takes place. 33. The method according to claim 32, characterized in that the esterification with an active ester, preferably Isopropenyl and / or vinyl acetate takes place. 34. The method according to claim 32 or 33, characterized in that the esterification in the presence of an enzyme is selected from the group consisting of lipases and esterases, preferably a lipase. 35. The method according to any one of claims 32 to 34, characterized in that lipases from Pseudomonas cepacia and / or Candida antarctica can be used. 36. The method according to any one of claims 32 to 34, characterized in that esterases from Pseudomonas fluorescens and / or Streptomyces diastatochromogenes can be used. 37. The method according to claim 35, characterized in that lipases from Pseudomonas cepacia are used. 38. The method according to any one of claims 22 to 27, characterized in that the production of non-at the α-hydroxy position racemic compounds of the general formula I or IV by racemate-cleaving enzymatic hydrolysis of compounds of type IV takes place. 39. The method according to claim 38, characterized in that the hydrolysis in the presence of an enzyme selected from the Group consisting of lipases and esterases. 40. The method according to claim 38 or 39, characterized in that lipases from Pseudomonas cepacia and / or Candida antarctica can be used. 41. The method according to claim 38 or 39, characterized in that esterases from Pseudomonas fluorescens and / or Streptomyces diastatochromogenes can be used. 42. The method according to claim 38 or 39, characterized in that recombinant pig liver esterase is used as the enzyme becomes. 43. The method according to any one of claims 22 to 42, characterized in that a diastereomer separation of compounds of general formulas I, II, III and / or IV, their α-hydroxy group by a non-racemic chiral acyl group (R ³ = R *) is protected by crystallization, cocrystallization, distillation, sequential extraction, e.g. B. HSCCC (high speed counter current chromatography) and / or chromatographic separation, preferably by chromatographic separation, particularly preferably by liquid chromatographic methods on achiral solid phases such as silica gel. 44. The method according to any one of claims 22 to 43, characterized in that the compounds of general formula IV to compounds of general formula V


be implemented
where Z is selected from the group consisting of = O, = N-Nu, = CH-hetaryl, = CH-aryl and = PR ₃ ; and preferably = CH-hetaryl; and is particularly preferably selected from the group consisting of (E) - (2-methylthiazol-4-yl) -CH = and (E) - (2-methyloxazol-4-yl) - CH =; where all groups Z can be in (E) form, (Z) form or as (E / Z) mixture. 45. The method according to claim 44, characterized in that the reaction is carried out by Wittig type reactions. 46. The method according to claim 44 or 45, characterized in that the reaction to a compound having the general formula


he follows. 47. The method according to any one of claims 22 to 46, characterized in that all reactions on separate diastereomers and / or on the mixture of diastereomers. 48. The method according to any one of claims 22 to 47, characterized in that the compounds of general formulas I, II, IV and / or V under anhydrous, strongly basic conditions, preferably with the bases Trialkylamine, DBU, DBN and / or polymeric strong bases can be racemized. 49. Use of the compound according to one of claims 1 to 21 as a building block, in particular as a C ₁₅ -C ₁₆ -containing building block for the production of epothilones and their derivatives. 50. Use of the method according to one of claims 22 to 48 in the Manufacture of epothilones and their derivatives. 51. Connection produced by a method according to one of claims 22 to 48.