DE10051136A1 - 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 epothilone synthesis building blocks, processes for the production, and the use of the synthesis building blocks for the production of epothilones and their derivatives. Epothilones are natural substances with an extraordinary biological effect, e.g. B. as mitotic inhibitors, microtubule-modifying agents, cytotoxics or fungicides, in particular they have paclitaxel-like properties and surpass paclitaxel (Taxol®) in some tests in terms of activity. They are currently in clinical trials to treat cancer.

Epothilones, especially Epothilon B and D, are characterized by a C7-C18 (methyl) unit in the "north half", which is structurally a modified polyprenyl (Polyisoprene) chain corresponds; and by a C1-C6 (methyl) unit in the "south half", the from aldol type reactions, e.g. B. according to German Offenlegungsschrift No. 197 01 758.4, (1998). The terms structural element, synthesis building block and building block are used used synonymously. The numbering follows that of the epothilone (see drawing).

In particular, substituents and especially methyl branches are in the naming of Building blocks as the C (number) -C (number) range are usually not mentioned separately, but are explicitly - but not necessarily - included.

The structural element C7-C16-Me of the epothilones or subunits, in particular C7-C15 building blocks, have hitherto been synthesized with prenyl derivatives from nucleophilic prenyl metal derivatives, e.g. B. according to German Offenlegungsschrift No. 197 13 970.1 (1998). Although this method has clear advantages over other methods for constructing this structural element, it is disadvantageous that prenyl metal species, preferably of the barium, have to be generated. This is expensive, complex and also leads to by-products, e.g. B. by allyl rearrangement (S _N 2 'attack) during the reaction. Likewise, either oxidation at C15 or C16 is required to introduce the oxygen function, or this function must be brought along appropriately, which requires relatively complex building blocks, which also often pose problems for further syntheses.

In the case of structural element C1-C6-Me of the epothilones, the state of the art has often resulted a problem connecting to C7. This should be syn-specific. In previous Processes that primarily use enolates generated with bases are secondary reactions due to of these reagents possible and / or the partners can only use certain Protecting groups or by suitable influence by the stereo center at C3 in sufficient yield can be linked correctly.

The north half

We have now surprisingly found that natural, commercial or literature-known prenyl derivatives, in particular geranyl, neryl, linaloyl and farnesyl derivatives (II, III), preferably starting from the alcohols, acetates or halides, in electrophilic synthetic building blocks of type II for Epothilones and their derivatives can be converted or used as such in order to be linked by simple nucleophilic substitution with a C15-C16 structural element IV - in particular of the acetoacetate type, very particularly IVb - which already has the appropriate one at C15 Oxidation level or substitution Y has. The term derivatives includes homologous, analog and Nor compounds, preferably also variants with further substituents on the main chain or in the C15-C16 element. Depending on the starting substance, there is no further CC for the areas C7-C10 and / or C11-C14 (one prenyl unit), but especially for C7-C14 (two prenyl units, e.g. from nerol, geraniol and linalool, Y = OH) - Link required. The stereochemistry at C12-C13 can be predetermined by the choice of the starting material (E- or Z-prenyl compound).

B ¹ , B ² single and 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: H, alkyl, aryl, alkyl-aryl (CH ₂ aryl, C ₂ H ₄ aryl etc.), vinyl, 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, phenyl, benzyl, particularly preferably H, methyl, ethyl; or combinations thereof
R ': like R
R ": like R, very particularly preferably methyl
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: H; OH; or halogen or other usual leaving groups and their combinations; preferably Cl, Br, I, O-tosyl, methyl sulfonate, trifluoromethyl sulfonate, alkanoates and aryl carboxylates; particularly preferably H, Cl, Br;
Y: S, NH, NPG, NR, O, preferably NH, NPG, NR, O, particularly preferably O
Nu: R, O-PG, OR, N (PG) ₂ , NR ₂ , SPG, SR, SePG, SeR, CN, N ₃ , aryl, heteroaryl, preferably R, OPG, OR, N (PG) ₂ , NR ₂ , particularly preferably H, alkyl;
Z: -OH, -O-PG, -OR, = 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 =
EWG: Designates groups corresponding to E (see above) and other customary electron-withdrawing functional groups such as CN, CO-R, alkylphosphonate, SO ₂ -R, SO ₂ OR, CF ₃ , CCl ₃ , NO ₂ ; preferably CN, CO-R, CO-NR ₂ ; particularly preferably CO ₂ R, CO ₂ PG. With Z = (2-methylthiazol-4-yl) -CH = or (2-methyloxazol-4-yl) -CH =, EWG can also be hydrogen (EWG = H).
Alkyl denotes hydrocarbons, also branched isomers, with 1-8 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 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; protecting groups which protect adjacent or divalent groups (PG ₂ ) to form 5-7-membered rings simultaneously, such as succinyl, phthalyl, methylene, acetonide; and / or combinations of all of the aforementioned protective groups.

In Ib Z 'preferably = O, 2-methylthiazol-4-ylmethylene, 2-methyloxazol-4-ylmethylene, X = Cl, Br, particularly preferably H; PG = t-Bu

X: s. Formula I, except H, preferably: OH, OAc, OTs, Cl, Br, particularly preferred as electrophilic building blocks OTs, Cl, Br

C15-16 building block IV. For substituents see. I.
For IVa: particularly preferably X = H, R = t-Bu, R "= Me.

Synthesis building blocks produced according to the invention have the general structural formula I, preferably the formula Ia, particularly preferably the formula Ib, and can in racemic or non-racemic form, or as individual diastereomers or Diastereomer mixture are present.

The structural elements I and IV can preferably as products or as Intermediates are used in the synthesis of active ingredients. In addition, the structural elements I according to the invention for the synthesis of polyketide and terpenoid Natural products or derivatives of polyketide and terpenoid natural products are used, preferably for macrocyclic active ingredients such as epothilones and their derivatives including Stereoisomers and / or homologues, Nor compounds, and / or as whole or in part inverted elements, where they are preferably as C7-C15 and C7-C16 or special can preferably serve as C7-C14 building blocks of the ring, if necessary additionally Wear pre-formed elements or the entire side chain at C15 of the ring can.

These building blocks, hereinafter also referred to as synthesis building blocks, are preferably enriched in an enantiomeric and / or diastereomeric form, especially preferably the forms corresponding to the natural epothilones.

Furthermore, compounds according to the invention having the general structural formula I and IV, in which the functional groups are wholly or partly by PG were protected.

The compounds of type I (structural element) according to the invention, and their Stereoisomers have been based on commercially available or known Process representable starting materials II-III by C-C linkage with 2-oxy-substituted-1,3-diaactivated methylene compounds IV, preferred 2-acyloxy-1,3-dicarbonyl compounds, particularly preferably with 2-acyloxy acetoacetates, specifically preferably IVa, obtained, wherein particularly basic reaction conditions are advantageous.

It was also found that modifications to C7, C8 and C9 of these Have connections carried out, in particular by oxidation, for example at C7, Reduction. From, for example, C8-9, or nucleophilic addition to, for example, C9  E = EEC or substitution, for example at C7; Modifications to C12-13, for example epoxidation; Modifications to C16, for example alkenylation, such as the Wittig-type reaction with Z = O; and modifications to C15 such as removing EWG, for example decarboxylation; Transesterification or saponification / esterification of Y.

The aforementioned substituents, protective groups, types of bonds B and / or stereoisomers, as well as the order of linking or modification, as far as it is chemical it makes sense to change and combine as desired ("Combinatorial Chemistry, Multiple Route Combinations ").

The compounds of type I according to the invention, but also of type I (with EEC = H) usually have at least one in positions 7 and 15 and / or 16 Substituents that are not hydrogen or R, preferably those that are suitable, links with C17-C20 side chain building blocks and especially with To bring C1-C6 building blocks or their starting materials, such as z. B. in the German. Publication 197 1975 v. 1998 are listed, particularly preferably by Ester or lactone formation of an epothilone C1 building block with C15 and / or aldol or Reformatsky-type reaction of an epothilone C6 building block with C7 and / or linkage a C17-C20 side chain building block with C16, unless the latter has already been used in an earlier one Stage was tied up.

Compounds of the structural element of type I with E = CH ₂ OH, CHO, CO ₂ R can be prepared by oxidizing compounds I, preferably Ia, particularly preferably neryl derivatives, preferably in the 7-position. For this purpose, sensitive positions that should not be oxidized can be protected in the usual and known manner (see below), alcohols preferably as silyl ethers or alkanoates, carboxylic acid groups preferably as esters. The oxidation takes place according to the regulations, such as. B. in HUDLICKY 1990 (Oxidations in Organic Chemistry, 0-8412-1781-5 / 90) are listed. The 7-position is oxidized, preferably with selenium reagents, particularly preferably catalytically with selenium dioxide / peroxides. It was found that, depending on the process and the selected amount of selenium dioxide, alcohols (E = CH ₂ OH) or aldehydes (E = CHO) were initially formed. Further oxidation of the alcohols to the aldehyde, preferably with activated DMSO, but also reduction and substitution by customary methods make further substituents E accessible. Further oxidation of the aldehydes, e.g. B. with NaClO ₂ or air / catalyst, provides carboxylic acids. The allyl alcohols obtained from the commercial prenyl alcohols or by the above processes can be converted into an activated form by known processes, preferably into allyl halides, sulfonates or carboxylates, particularly preferably into C7 and C14 halides of the compounds I or II and protected derivatives thereof ,

Further modifications can be made to the double bonds. For example, these can be converted into single bonds, epoxides and cyclopropanes by processes known from the literature. The reduction is achieved using known processes, preferably hydride donors and particularly preferably catalytic processes, and asymmetrical variants are used. A differentiation of the double bonds, insofar as it does not already exist through substitution patterns of the starting materials, can be done electronically, e.g. B. by suitably chosen adjacent protective groups (electron-withdrawing or -delivering), or preferably sterically, for. B. by choosing a suitable order of the prenyl modifications described in the patent. In particular, it was found that the C8-C9 double bond can be selectively reduced using suitable groups EEC, in particular the tert-butyl carboxylates (CO ₂ t-Bu). A remaining C12-13 double bond can e.g. B. be selectively epoxidized with peracids. If the C8-9 double bond is electronically substituted (E = oxomethyl derivatives, preferably CO ₂ R, CHO), nucleophiles can be selectively introduced by the Michael reaction in position C9, preferably simple alkyl cuprates, alcohols and amines.

The reductions, nucleophilic additions, epoxidations and Cyclopropanations of the double bonds, or combinations thereof, can be suitable protected prenyl derivatives I are carried out according to methods known from the literature. So far Chemically meaningful, some of these modifications can also be done with a single or double to C1 (also with EWG = H) linked C1-C6 building block, preferably the Epoxidation of the C12-C13 double bond.

It has also been found that compounds of type I, preferably Ia Have type I compounds with EWG = H transferred. Particularly preferably used one compounds I with PG = t-butyl, especially Ib, under acid catalysis in one step dealkylcarboxylation to corresponding compounds I with EWG = H. The latter can be also link with C1-C6 blocks.

In the method according to the invention, the functional groups of the Compound of type I-IV, preferably of type Ia, and of intermediates in their protected form transferred (M = PG). Suitable protecting groups are: allyl, benzyl, Methyl, ethyl, t-butyl, activated methylene derivatives such as methoxymethyl, 1-oxacycloalkyl,  Silyl, in the latter preferably trialkylsilyl; and - mainly for alcohol functions - too Acyl protecting groups, in the latter particularly preferably acetyl, propionyl and benzoyl and their derivatives. Also such protecting groups, the neighboring groups Y at the same time protect: acetonides, methylene, cyclodiacyl and those which protect carbonyl groups, especially acetals and cyclic acetals (O and S). More for the patented claimed protective groups are from GREENE / WUTS 1991 (Protective Groups in Organic Synthesis, ISBN 0-471-62301-6), to which express reference is made is taken. Combinations of the protective groups mentioned.  

The southern half

According to the invention, the compounds of type VI are used for the southern half and VII in question. It has been found that compounds of type V are also suitable C3-C6 building blocks, and that these by the reaction of 2-haloacyl halides with Enamine of isobutyraldehyde and subsequent hydrolysis and acetalization to let. It has also been found that activated compounds of the type VI in the C6 position and V, easily from compounds of type VII and Va by oxidation, in particular by electrophilic halogenation, especially with tertiary or quaternary Ammonium perhalides are extremely light and can be obtained in good yield. It it has been found that these compounds work well on C7 etc. building blocks, e.g. B. Type I can be attached, preferably mediated by low-valent metal ions or metals in Reformatsky-type reactions as in German Offenlegungsschrift No. 197 01 758.4, Germany explained in 1998.

It has also been found that the reaction proceeds to an extraordinarily high degree syn-selective and aldehyde-selective, which makes it possible to convert Type I substances efficiently, especially those in which Z is a ketone or a hetarylalkylidene side chain. A particular advantage of the patented method is that the functionalities can be used to a large extent without protection, e.g. B. an ester group as C1 and a keto group at C16.

Links between north and south half

It was found according to the invention that the links between the north and south halves were found the procedures mentioned in the previous section, see p. Examples and claims Aldol reactions, preferably of the Reformatsky type, particularly preferably with chromium (II) salts, between C6-C7 or C2-C3, or successively at both points, linked together or - with pre-esterified building blocks, can be cyclized. This completely new method enables cyclization with high syn selectivity and chemoselectivity. Open chain Compounds can also be cyclized by macrolactonization according to known methods become.

On the different stages during building block synthesis as well Macrocyclic synthesis can be modified and substituted. So it was found that there are modifications to C7, C8 and C9 of these building blocks and to suitable ones Have intermediate connections made on the way to the macrocycle, in particular Oxidation, preferably at C7, reduction, preferably at. C8-9, or nucleophilic addition preferably at C9 with E = EWG or substitution preferably at C7; Modifications to C12-13, preferred epoxidation; Modifications to C 16, preferably to alkenylation, particularly preferred Willig type reaction with Z = O; and modifications to C15, preferably removal from EEC, particularly preferably by decarboxylation; Transesterification or Saponification / esterification of Y. The aforementioned substituents, protective groups, Binding types B and / or stereoisomers, as well as the order of linking or Modifications can, as far as it makes chemical sense, be changed and combined as desired become "Combinatorial Chemistry, Multiple Route Combinations".  

EXAMPLES

Unless explicitly stated otherwise, the specified connections may are also mixtures of isomers, (racemates, and / or diastereomers).

Enantiomerically enriched compounds are usually indicated by a Displayed. If necessary, the products obtained were in the state of the Technically known cleaning processes cleaned.

1. tert-Butyl-2-bromoacetoacetate

N-bromosuccinimide (58.7 g, 330 mmol) was added in portions to a solution of tert-butyl acetoacetate (49.0 ml, 47.5 g, 300 mmol) in acetone (30 ml). The suspension obtained was stirred for one hour at ambient temperature and then filtered. The filtrate was concentrated in vacuo and the residue was taken up in 300 ml of petroleum ether. After washing three times with 100 ml of water each time, the solution was dried over Na ₂ SO ₄ and filtered. The product was then obtained by concentration in vacuo.

2. tert-Butyl-2-acetoxyacetoacetate

A solution of glacial acetic acid (10.6 ml, 186 mmol) in DMF (169 ml) was neutralized with triethylamine (25.8 ml, 186 mmol) while cooling with ice. To the triethylammonium acetate solution thus obtained, tert-butyl-2-bromoacetoacetate (40.0 g, 169 mmol) was added dropwise at 0 ° C. The ice bath was removed after the addition was complete and the reaction mixture was stirred at room temperature for two hours. The mixture was then quenched with water (280 ml) and extracted with ethyl acetate (3 × 215 ml). The organic phases were combined and washed with both water (3 × 215 ml) and concentrated NaCl solution (1 × 215 ml). After drying over Na ₂ SO ₄ , filtering and concentrating in vacuo, the product oil was obtained, which was purified by double distillation at 12 mbar and 128 ° C.

3. (4Z) -2-acetoxy-2-acetyl-5,9-dimethyl-deca-4,8-dienoic acid tert-butyl ester

tert-Butyl-2-acetoxyacetoacetate (19.5 g, 90 mmol) was slowly added dropwise to a suspension of NaH (2.59 g, 108 mmol) in DMF (180 ml) at 0 ° C. After gas evolution was complete, neryl bromide (19.6 g, 90 mmol) was slowly added dropwise at 0 ° C. Finally the ice bath was removed and stirred at ambient temperature for 16 hours. The yellow solution obtained was diluted with diethyl ether (750 ml) and washed with water (3 × 200 ml) and concentrated NaCl solution (1 × 200 ml). After drying over Na ₂ SO ₄ , filtering and concentrating in vacuo, the product was obtained.

4. (4Z) -2-acetoxy-2-acetyl-5,9-dimethyl-10-hydroxy-deca-4,8-dienoic acid tert-butyl ester

Finely powdered selenium dioxide (0.158 g, 1.42 mmol) was suspended in DCM (50 ml). A 70% tert-butyl hydroperoxide solution (10.2 g, 79.5 mmol) was then added and the mixture was stirred 30 minutes at ambient temperature. Finally 10.0 g (28.4 mmol) (4Z) -2-acetoxy-2-acetyl-5,9-dimethyl-deca-4,8-dienoic acid tert-butyl ester added and at Ambient temperature stirred for 48 hours. After concentration in vacuo, 50 ml Toluene added and removed in vacuo (this serves to remove excess tert-Butylhydro peroxide). This was repeated three times in total and the product obtained was determined by means of flash chromatography (parameters of the chromatography column: 5.0 × 19.5 cm, Ethyl acetate / petroleum ether = 1: 2) separated.

5. Enantiomerically enriched (4Z) -2-acetoxy-2-acetyl-5,9-dimethyl-10-hydroxy-deca-4-enoic acid tert-butyl ester

7.94 g (21.6 mmol) of (4Z) -2-acetoxy-2-acetyl-5,9-dimethyl-10-hydroxy-deca-4,8-dienoic acid tert-butyl ester were dissolved in 15.0 ml of absolute methanol and 750 µl demineralized water added. The solution obtained was degassed using three freeze-thaw cycles. Then 185 mg Ru (R-BINAP) (OAc) ₂ and a magnetic stir bar were added and the lemon-yellow solution obtained was transferred to an autoclave. The nitrogen atmosphere was displaced from the autoclave by filling and releasing hydrogen gas (5.0 quality) three times. Finally, a pressure of 100 bar hydrogen gas (5.0 quality) was applied and the mixture was stirred for 25 hours at ambient temperature. The gas was released from the autoclave and the solution was concentrated in vacuo. The remaining product was purified by means of flash chromatography (parameters of the chromatography column: 4.5 × 25.0 cm, ethyl acetate / petroleum ether = 1: 2).

6. Enantiomerically enriched 3-acetoxy-11-hydroxy-6,10-dimethyl-5-undecen-2-one

1,032 g (2.79 mmol) (95) (42) -2-acetoxy-2-acetyl-5,9-dimethyl-10-hydroxy-deca-4-enoic acid tert-butyl ester were dissolved in 28 ml DCM and 2.80 ml TFA added. After stirring for two hours at ambient temperature, all volatile constituents were removed in vacuo and the remaining brown oil was dissolved in 28.0 ml of methanol. 5.6 ml of saturated NaHCO ₃ solution were then added, and the suspension obtained was stirred at ambient temperature for 140 minutes. After adding 200 ml of ether, the organic phase was washed twice with 50 ml of demineralized water and once with 50 ml of concentrated NaCl solution and then dried over Na ₂ SO ₄ . After filtering and concentrating in vacuo, the product was obtained, which was purified by means of flash chromatography (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 2: 3).

7. Enantiomerically enriched 3-acetoxy-11-tert-butyl-dimethylsilyloxy-6,10-dimethyl-5-undecen-2-one

528 mg (1.95 mmol) of 3-acetoxy-11-hydroxy-6,10-dimethyl-5-undecen-2-one were added in 10.0 ml absolute DCM dissolved and with both 541 µl (395 mg, 3.90 mmol) triethylamine as also added 12 mg (0.10 mmol) DMAP. The solution was cooled using an ice bath and stirred for five minutes. Thereafter, 368 mg (2.44 mmol) of TBDMSCl were added at once added and the solution obtained first at 0 ° C and finally at 14 hours Ambient temperature stirred.

A colorless suspension was obtained, which was cooled to 0 ° C. before finally adding 460 μl of methanol and stirring for 30 minutes. 15 ml of diethyl ether and 15 ml of saturated ammonium chloride solution were then added and the mixture was stirred vigorously. The aqueous phase was extracted twice with 10 ml of diethyl ether and the organic phases were combined. It was sat with 15 ml. Washed NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The remaining product was purified by means of flash chromatography (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1:10).

8. 3-acetoxy-11- (tert-butyldimethylsilanyloxy) -2,6,10-trimethyl-1- (2-methyl- thiazol-4-yl) -undeca-1,5-diene

A solution of 524 mg (1.50 mmol) 2-methyl-4- (methyl-tributylphosphonium bromide) -1,3-thiazole in 10.0 ml abs. THF was cooled to -63 ° C. and 749 μl (1.50 mmol) of a 2.0 M sodium hexamethyldisilazide solution in THF were slowly added dropwise. After stirring for 15 minutes, a solution of 480 mg (1.25 mmol) of 3-acetoxy-11-tert-butyl-dimethylsilyloxy-6,10-dimethyl-5-undecen-2-one in 4.0 ml of THF was slowly added dropwise. After stirring for 30 minutes at -63 ° C, the solution was warmed to 55 ° C and stirred for a further hour. The heating bath was then removed and 20 ml of saturated NH ₄ Cl solution were added. The phases were separated and the aqueous phase extracted three times with 20 ml of diethyl ether. The organic phases were combined and washed three times with 20 ml of demineralized water and once with 20 ml of saturated NaCl solution. Finally, it was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The remaining product was purified by means of flash chromatography (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 4).

9. Enantiomerically enriched 11- (tert-butyl-dimethyl-silanyloxy) -2,6,10- trimethyl-1- (2-methyl-thiazol-4-yl) -undeca-1,5-dien-3-ol

221 mg (0.461 mmol) of 3-acetoxy-11- (tert-butyl-dimethyl-silanyloxy) -2,6,10-trimethyl-1- (2-methyl-thiazol-4-yl) -undeca-1,5 -diene and 64 mg (0.461 mmol) of K ₂ CO ₃ were stirred in 5.5 ml of absolute methanol for two hours at ambient temperature. 30 ml of ethyl acetate were then added and the organic phase was washed with demineralized water (3 × 10 ml) and with saturated NaCl solution (1 × 10 ml), dried over Na ₂ SO ₄ , filtered and finally concentrated in vacuo. A product was obtained which was purified by flash chromatography (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 4).

10. (4S) -3 - [(3S) -4,4-dimethyl-1,5-dioxo-3-hydroxyheptyl] -4-benzyl-2-oxazolidinone

9.0 ml (14.4 mmol) of butyllithium (1.6 M in hexane) were added dropwise to 2.55 g (14.4 mmol) of (S) -4-benzyl-2-oxazolidinone in 50 ml of tetrahydrofuran at -78 ° C. 1.25 ml (14.4 mmol) bromoacetyl bromide was added all at once. The mixture is stirred at -78 ° C. for 30 min and warmed to room temperature. 2.03 g (15.8 mmol) of 2,2-dimethyl-3-oxopentanal, 4.42 g (36.0 mmol) of CrCl ₂ and 193 mg (1.44 mmol) of LiI are added to the glove box. After a reaction time of eight hours at 20 ° C., 20 ml of saturated NaCl solution were added and the dark green two-phase system was stirred for 15 minutes. The organic phase was separated and the aqueous phase was extracted three times with diethyl ether. The combined organic phases were washed three times with demineralized water and once with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The product was chromatographed on silica gel with ethyl acetate / petroleum ether (1: 1).

11. (4S) -3 - [(3S) -4,4-dimethyl-1,5-dioxo-3- (tert-butyldimethylsilanyloxy)] - 4-benzyl-2-oxazolidinone

1.50 g (4.32 mmol) of (4S) -3 - [(3S) -4,4-dimethyl-1,5-dioxo-3-hydroxyheptyl] -4-benzyl-2-oxazolidinone in 20 ml of absolute DCM were added at 0 ° C under argon 1.11 ml (9.50 mmol) of freshly distilled 2,6-lutidine and 1.49 ml (6.48 mmol) (tert-butyl-dimethylsilyl) - trifluoromethanesulfonate. After stirring for 2.5 hours at 0 ° C., 4.0 ml of 2 N NaOH solution were added and the mixture was diluted with 30 ml of DCM. After phase separation, the organic phase was washed twice with 30 ml of 2N hydrochloric acid and once with saturated NaCl solution. It was dried with MgSO ₄ , concentrated in vacuo and the product was chromatographed on silica gel with ethyl acetate / petroleum ether (1: 4).

12. (3S) -3- (tert-Butyl-dimethyl-silanyloxy) -4,4-dimethyl-5-oxo-heptanoic acid

To 742 mg (1.61 mmol) of (45) -3 - [(35) -4,4-dimethyl-1,5-dioxo-3- (tert-butyl-dimethyl silyloxy)] - 4-benzyl-2-oxazolidinone in 36 ml of tetrahydrofurane / water (3: 1) were added 1.11 ml (9.66 mmol) of hydrogen peroxide solution (30%) and 135 mg (3.22 mmol) of lithium hydroxide hydrate at 0 ° C. After stirring for one hour, 1.40 g of sodium sulfite in 20 ml of demineralized water were added. It was buffered with aqueous sodium bicarbonate solution, tetrahydrofuran was removed in vacuo and the aqueous solution was washed three times with 5.0 ml of DCM. The aqueous phase was acidified to pH 1 with HCl (10%) and extracted five times with 10 ml of DCM. The organic phases were dried over MgSO ₄ and the product was concentrated in vacuo.

13. (3S) -6-bromo-3- (tert-butyl-dimethyl-silanyloxy) -4,4-dimethyl-5-oxo-heptanoic acid

152 mg of a solution of 116 mg (0.383 mmol) of (35) -3- (tert-butyl-dimethyl-silanyloxy) -4,4-dimethyl-5-oxo-heptanoic acid in 3.8 ml of tetrahydrofuran were added at 0 ° C (0.403 mmol) phenytrimethylammonium bromide dibromide. After stirring for fifteen minutes, the ice bath was removed and stirred for an additional hour at ambient temperature. 5.0 ml of demineralized water were added to the suspension obtained. The aqueous phase was extracted three times with 8 ml of diethyl ether. The combined organic phases were washed with 10 ml of 1N HCl solution and with 10 ml of saturated NaCl solution, then dried over Na ₂ SO ₄ , finally filtered and concentrated in vacuo. The remaining oil was purified by flash chromatography (parameters of the chromatography column: 1.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 4 with 2% glacial acetic acid). Two fractions were isolated. Fraction 1 contained a single diastereomer, fraction 2 was a mixture of diastereomers.

14. 6-bromo-3- (tert-butyl-dimethyl-silanyloxy) -4,4-dimethyl-5-oxo-heptanoic acid 9- (tert-butyl-dimethyl-silanyloxy) -4,8-dimethyl-1- [1-methyl-2- (2-methyl-thiazol-4-yl) - vinyl] -non-3-enyl ester

127 mg (0.291 mmol) 11- (tert-butyl-dimethyl-silanyloxy) -2,6,10-trimethyl-1- (2-methyl- thiazol-4-yl) -undeca-1,5-dien-3-ol, 115 mg (0.291 mmol) (3S) -6-bromo-3- (tert-butyl-dimethyl- silanyloxy) -4,4-dimethyl-5-oxo-heptanoic acid and 7 mg (0.058 mmol) DMAP were in 1.60 ml of absolute DCM dissolved and cooled to 0 ° C. With stirring, 73 mg (0.378 mmol) EDCI added at 0 ° C. After stirring for ten minutes, the ice bath removed and stirred for 18 hours at ambient temperature. The solvent was in Vacuum removed and the product by means of flash chromatography (parameters of Chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 4) purified.

15. 6-bromo-3- (tert-butyl-dimethyl-silanyloxy) -4,4-dimethyl-5-oxo-heptanoic acid 9-hydroxy-4,8-dimethyl-1- [1-methyl-2- (2-methyl-thiazol-4-yl) -vinyl] -non-3-enyl ester

162 mg (0.202 mmol) 6-bromo-3- (tert-butyl-dimethyl-silanyloxy) -4,4-dimethyl-5-oxo-heptanoic acid 9- (tert-butyl-dimethyl-silanyloxy) -4, 8-dimethyl-1- [1-methyl-2- (2-methyl- thiazol-4-yl) vinyl] -non-3-enyl ester were dissolved in 6.0 ml of a 1: 1 mixture of DCM and MeOH dissolved and cooled to 0 ° C. After adding 47 mg (0.202 mmol) of CSA, the Solution stirred at 0 ° C for 2.5 hours. After adding 42 µl (31 mg, 0.303 mmol) Triethylamine, the solvents were removed in vacuo and the remaining product flash chromatography (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 2) cleaned.

16. 6-bromo-3- (tert-butyl-dimethyl-silanyloxy) -4,4-dimethyl-5-oxo-heptanoic acid 4,8-dimethyl-1- [1-methyl-2- (2-methyl-thiazol-4-yl) -vinyl] -9-oxo-non-3-enyl ester

119 mg (0.173 mmol) 6-bromo-3- (tert-butyl-dimethyl-silanyloxy) -4,4-dimethyl-5-oxo- heptanoic acid 9-hydroxy-4,8-dimethyl-1- [1-methyl-2- (2-methylthiazol-4-yl) vinyl] non-3- enyl esters were dissolved in 2.10 ml DCM and 700 µl DMSO and cooled to 0 ° C.

120 μl (885 mg, 0.865 mmol) of triethylamine were then added with stirring. After addition of 110 mg (0.692 mmol) of SO ₃ .pyridine complex, the mixture was stirred at 0 ° C. for 40 min. The mixture was then diluted with 30 ml of ethyl acetate and washed twice with 10 ml of demineralized water and once with 10 ml of saturated NaCl solution. The organic phase was dried over Na ₂ SO ₄ , then filtered and concentrated in vacuo. The product obtained was not further treated and could be used directly in the following reaction step.

17. 4- (tert-Butyldimethylsilanyloxy) -8-hydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2-methyl-thiazol-4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione [= 3-O- (tert-butyl-dimethyl-silanyl) -epothilone D]

A solution of 80 mg (0.117 mmol) of 6-bromo-3- (tert-butyl-dimethyl-silanyloxy) was added to a suspension of 35 mg (0.285 mmol) of CrCl ₂ and 30 mg (0.224 mmol) of LiI in 25 ml of dry tetrahydrofuran ) -4,4-dimethyl-5-oxo-heptanoic acid 4,8-dimethyl-1- [1-methyl-2- (2-methyl-thiazol-4-yl) vinyl] -9-oxo-non- 3-enyl ester in 5.0 ml of absolute tetrahydrofuran was added within 80 min using a syringe pump. After the addition was complete, the suspension obtained was stirred for a further two hours at ambient temperature.

The mixture was then quenched with 20 ml of semi-concentrated NH ₄ Cl solution and the organic phase was extracted with diethyl ether (5 × 15 ml). The organic phases were combined and washed twice with 15 ml of demineralized water and twice with 15 ml of saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. This gave 67 mg of a yellow oil.
This oil contained various 6,7,8,15-stereoisomeric macrocycles, three of which could be isolated in the following way.
Flash chromatography (parameters of the chromatography column: 1.0 × 20.0 cm, dieethyl ether / petroleum ether = 1: 2) allowed the isolation of several fractions, which were prepared by preparative HPLC on an Econosil C18 / 10 μ 10 × 250 mm column under isocratic conditions with 85% MeCN, 15 % Water (which contains 1% formic acid) could be further separated at 5.0 ml / min, and, inter alia, provided the following three 3-TBS-protected epothilone diastereomers.

17.1. Diastereomer A

Yield: 4 mg (0.0066 mmol, 6%) colorless oil
R _f

-Value: 0.30
retention time: 42.5 to 63 minutes
¹

H-NMR (250 MHz, CDCl ₃

, TMS):
δ = 0.04 (s, 3H, TBS), 0.13 (s, 3H, TBS), 0.89 (s, 9H, TBS), 1.05 (s, 3H, H-22 or H-23), 1.06 (d, J = 6.8 Hz, 3H, H-25), 1.15 (d, J = 6.9 Hz, 3H, H-24), 1.24 (s, 3H, H-22 or H-23), 1.28-1.58 (m, 6H), 1.69 (s, 3H, H-26), 1.95-2.10 (m, 1H, H-11), 2.07 (s, 3H, H-27), 2.05-2.60 (m, 4H), 2.70 (s, 3H, H-21), 3.10 (m, 1H), 3.50 (m, 1H), 4.41 (dd, J = 7.8 Hz, J = 3.1 Hz, 1H, H-3), 5.10-5.20 (m, 2H), 6.49 (s, 1H, H-17), 6.94 (s, 1H, H-19) ppm.
HRMS: calculated for C ₃₃

H ₅₆

NO ₅

SSi (MH ⁺

): 606.3648
found: 606.3650
[Α]

       22 | D     

= -5.4 °
C ₃₃

H ₅₅

NO ₅

SSi (605.95)

17.2. Diastereomer B

Yield: 7 mg (0.0116 mmol, 10%) colorless oil
R _f

-Value: 0.15 and 0.18
retention time: 24 to 36 minutes
¹

H-NMR (400 MHz, CDCl ₃

, TMS):
δ = 0.05 (s, 3H, TBS), 0.06 (s, 3H, TBS), 0.83 (s, 9H, TBS), 1.00 (d, J = 7.1 Hz, 3H, H-25), 1.08 (s, 3H , H-22 or H-23), 1.16 (d, J = 6.9 Hz, 3H, H-24), 1.24 (s, 3H, H-22 or H-23), 1.28-1.40 (m, 2H), 1.58 (br, 3H), 1.65 (s, 3H, H-26), 1.72-1.82 (m, 1H, H-8), 1.88-1.96 (m, 1H, H-11), 2.09 (d, J = 1.1 Hz, 3H, H-27), 2.20-2.32 (m, 2H, H-11 and H-14), 2.47 (dd, J = 16.8 Hz, J = 6.0 Hz, 1H, H-2), 2.54 ( dd, J = I 6.6 Hz, J = 5.0 Hz, 1H, H-2), 2.60-2.70 (m, 1H, H-14), 2.71 (s, 3H, H-21), 3.22 (qd, J = 6.9 Hz, J = 2.1 Hz, 1H, H-6), 3.81 (dd, J = 4.6 Hz, J = 2.1 Hz, 1H, H-7), 4.47 (t, J = 5.6 Hz, 1H, H-3 ), 5.13 (m, 1H, H-13), 5.28 (dd, J = 8.0 Hz, J = 3.5 Hz, 1H, H-15), 6.48 (s, 1H, H-17), 6.94 (s, 1H , H-19) ppm.
HRMS: calculated for C ₃₃

H ₅₆

NO ₅

SSi (MH ⁺

): 606.3648
found: 606.3663
[Α]

       22 | D     

= + 4.89 °
C ₃₃

H ₅₅

NO ₅

SSi (605.95)

17.3. Diastereomer C

Yield: 2 mg (0.0033 mmol, 3%) colorless oil
R _f

-Value: 0.09
retention time: 37.5 to 54.0 minutes
¹

H-NMR (400 MHz, CDCl ₃

, TMS):
δ = 0.01 (s, 3H, TBS), 0.10 (s, 3H, TBS), 0.83 (s, 9H, TBS), 1.05 (d, J = 6.7 Hz, 3H), 1.10 (d, J = 6.9 Hz, 3H), 1.13 (s, 3H), 1.16 (s, 3H), 1.20-1.40 (m, 2H), 1.50-1.65 (m, 3H), 1.69 (s, 3H, H-26), 1.70-1.80 ( m, 1H), 2.05-2.18 (m, 1H), 2.07 (d, J = 1.0 Hz, 3H, H-27), 2.45-2.55 (m, 1H), 2.67-2.75 (m, 1H) 2.71 (see , 3 H, H-21), 2.78 (d, J = 6.5 Hz, 2H, H-2), 3.21 (q, J = 6.9 Hz, 1H, H-6), 3.68 (d, J = 9.6 Hz, 1H, H-7), 3.75 (s, 1H, OH), 4.18 (t, J = 6.4 Hz, 1H, H-3), 5.02 (dd, J = 10.1 Hz, J = 2.0 Hz, 1H, H- 15), 5.15 (m, 1H, H-13), 6.55 (s, 1H, H-17), 6.95 (s, 1H, H-19) ppm.
[Α]

       22 | D     

= + 14.6 °
C ₃₃

H ₅₅

NO ₅

SSi (605.95)

18. 3-Acetoxy-11- (tetrahydro-pyran-2-yloxy) -6,10-dimethyl-5-undecen-2-one

324 mg (1.20 mmol) of a crude product of 3-acetoxy-11-hydroxy-6,10-dimethyl-5-undecen-2-one and 219 µl (202 mg, 2.40 mmol) of dihydropyran were mixed in 8.5 ml of DCM dissolved. After adding 30 mg (0.12 mmol) of pyridinium paratoluenesulfonate, the reaction mixture was stirred at ambient temperature for 18 hours. 25 ml of diethyl ether were then added, the organic phase obtained was washed once with 25 ml of semi-concentrated NaCl solution and dried over Na ₂ SO ₄ . After filtration and removal of the solvents in vacuo, the remaining product was purified by means of flash chromatography (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 4) on silica gel.

19. Acetic acid 4,8-dimethyl-1- [1-methyl-2- (2-methylthiazol-4-yl) vinyl] -9- (Tetrahydro-pyran-2-yloxy) -non-3-enyl ester

A solution of 200 mg (0.57 mmol) 2-methyl-4- (methyl-tributylphosphonium bromide) -1,3-thiazole in 5.0 ml abs. THF was cooled to -63 ° C. and 286 μl (0.57 mmol) of a 2.0 M sodium hexamethyldisilazide solution were added dropwise. After stirring for 15 minutes, a solution of 167 mg (0.48 mmol) of 3-acetoxy-11- (2-tetrahydropyranyloxy) -6,10-dimethyl-5-undecen-2-one in 2.0 ml of THF was slowly added dropwise. After stirring for 15 minutes at -63 ° C, the solution was warmed to 55 ° C and stirred for an additional hour. The heat bath was then removed and 10 ml of saturated NH ₄ Cl solution were added.

Triple extraction with 10 ml ether, washing the combined ether phases with demi water (3 × 10 ml) and with saturated NaCl solution (1 × 10 ml), drying over Na ₂ SO ₄ , filtration and removal of the solvent in vacuo gave a product , which was purified by means of flash chromatography (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 4) on silica gel.

20. Acetic acid 9-hydroxy-4,8-dimethyl-1- [1-methyl-2- (2-methylthiazol-4-yl) vinyl] - non-3-enyl ester

A solution of 238 mg (0.53 mmol) of acetic acid 4,8-dimethyl-1- [1-methyl-2- (2-methylthiazol-4-yl) vinyl] -9- (tetrahydro-pyran-2-yloxy ) -non-3-enyl ester and 13 mg (0.053 mmol) pyridinium paratoluenesulfonate in 5.0 ml 96% ethanol was stirred at 55 ° C for eight hours. After concentration in vacuo, the residue was taken up in 25 ml of diethyl ether. The organic phase was washed with 5% NaHCO ₃ (2 × 10 ml) and with concentrated NaCl solution (1 × 10 l), then dried over Na ₂ SO ₄ , finally filtered and concentrated in vacuo. The remaining product was purified by means of flash chromatography (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 2) on silica gel.

21. Acetic acid 4,8-dimethyl-1- [1-methyl-2- (2-methylthiazol-4-yl) vinyl] -9-oxo-non-3- enyl

26 µl (38 mg, 0.30 mmol) oxalyl chlorides in 2.0 ml abs. DCM dissolved and at -63 ° C cooled. After adding a solution of 42 µl (46 mg, 0.59 mmol) abs. DMSO in 0.5 ml abs. DCM was stirred for 10 min at -63 ° C and a solution of 99 mg (0.27 mmol) acetic acid 9-hydroxy-4,8-dimethyl-1- [1-methyl-2- (2-methylthiazol-4-yl) vinyl] non-3-enyl ester in 1.0 ml Section. DCM slowly added dropwise. After stirring for 30 minutes at -68 ° C, 187 ul (137 mg, 1.35 mmol) triethylamine added. In the end they let up Thaw the ambient temperature and stir at this temperature for one hour.

After adding 5.0 ml of water, the phases were separated and the aqueous phase was extracted twice with 5.0 ml of DCM. The combined organic phases were washed with saturated NH ₄ Cl solution (2 × 4.5 ml), with water (1 × 4.5 ml) and with concentrated NaCl solution (1 × 4.5 ml). After drying over Na ₂ SO ₄ , filtration and concentration in vacuo, the product obtained was purified by means of flash chromatography (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 2) on silica gel.

22. Acetic acid 1-acetyl-9-hydroxy-13,13-dimethoxy-4,8,10,12,12-pentamethyl-11-oxo-tridec-3-enyl ester

107 mg (0.86 mmol) CrCl ₂ and 54 mg (0.4 mmol) LiI were dissolved in 1.0 ml abs. THF suspended and with a solution of 103 mg (0.38 mmol) acetic acid 1-acetyl-4,8-dimethyl-9-oxo-non-3-enyl ester in 1.0 ml abs. THF offset. 102 mg (0.40 mmol) of 4-bromo-1,1-dimethoxy-2,2-dimethyl-pentan-3-one are then added all at once. After stirring for three hours at ambient temperature, the mixture was saturated with 2.0 ml of oxygen-free. NaCl solution quenched and the aqueous phase extracted five times with 2.0 ml of a 5: 1 diethyl ether / pentane mixture. The combined organic phases were washed three times with 2.0 ml of saturated NH ₄ Cl solution and dried over Na ₂ SO ₄ , filtered and concentrated. The remaining product was purified by means of flash chromatography (parameters of the chromatography column: 2.0 × 20.0 cm, ethyl acetate / petroleum ether = 1: 1) on silica gel. Two diastereomers were obtained.

syn / anti diastereomer

Yield: 97 mg (0.22 mmol, 58%) colorless oil
¹

H-NMR (250 MHz, CDCl ₃

, TMS):
δ = 0.84 (d, 3H, J = 6.7 Hz), 1.02 (d, 3H, J = 7.0 Hz), 1.15 (s, 3H), 1.18 (s, 3H), 1.30-1.90 (m, 5H), 1.70 (pseudo-doublet, 3H, J = 1.3 Hz), 1.99-2.05 (m, 2H), 2.13 (s, 3H), 2.15 (s, 3H), 2.45-2.51 (m, 2H), 3.27 (qd, 1H . J = 7.0 Hz, J = 1.6 Hz), 3.37 (dd, 1H, J = 9.1 Hz, J = 1.5 Hz), 3.47 (br, 1H, OH), 3.49 (s, 3H), 3.51 (s, 3H ), 4.28 (s, 1H), 4.98 (m, 1H), 5.09 (m, 1H) ppm.
¹³

C-NMR (62.5 MHz, CDCl ₃

, TMS):
d = 9.72 (q), 15.48 (q), 19.59 (q), 19.93 (q), 20.67 (q), 23.46 (q), 25.03 (t), 26.56 (q), 29.00 (t), 32.26 (t ), 32.74 (t), 35.31 (d), 41.29 (d), 54.11 (s), 58.59 (q), 58.83 (q), 74.69 (d), 78.59 (d), 111.21 (d), 117.80 (d ), 139.87 (s), 170.54 (s), 205.20 (s), 221.00 (s) ppm.

syn / syn diastereomer

Yield: 58 mg (0.13 mmol, 35%) colorless oil
¹

H-NMR (250 MHz, CDCl ₃

, TMS):
δ = 0.96 (d, 3H, J = 6.6 Hz), 1.07 (d, 3H, J = 6.9 Hz), 1.16 (s, 3H), 1.18 (s, 3H), 1.20-1.70 (m, SH), 1.71 (pseudo-doublet, 3H, J = 1.2 Hz), 1.94-2.03 (m, 2H), 2.14 (s, 3H), 2.16 (s, 3H), 2.46-2.52 (m, 2H), 3.03 (m, 1H ), 3.24 (qd, J = 6.9 Hz, J = 3.8 Hz), 3.48 (s, 3H), 3.51 (s, 3H), 4.30 (s, 1H), 4.99 (m, 1H), 5.11 (m, 1H ) ppm.
¹³

C-NMR (62.5 MHz, CDCl ₃

, TMS):
δ = 11.54 (q), 15.02 (q), 19.52 (q), 20.11 (q), 20.68 (q), 23.48 (q), 25.04 (t), 26.67 (q), 29.05 (t), 32.07 (t ), 33.16 (t), 35.32 (d), 42.36 (d), 53.95 (s), 58.45 (q), 59.00 (q), 74.81 (d), 78.50 (d), 111.21 (d), 117.96 (d ), 139.67 (s), 170.52 (s), 205.35 (s), 220.22 (s) ppm.

Claims (42)

1. Structural elements, particularly suitable as a building block for the synthesis of polyketides, terpenoids, and / or epothilones and their derivatives, characterized in that the structural element is a compound having the general formula I, IV, IVa, V, Va, VI; VII, IXa and / or IXb,
wherein:
B ¹ , B ² , B ³ : single and 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 and B ³ as a single bond; and / or combinations thereof;
R: H, alkyl, aryl, alkyl-aryl (CH ₂ aryl, C ₂ H ₄ aryl etc.), vinyl, 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, phenyl, benzyl, particularly preferably H, methyl, ethyl; or combinations thereof;
R ': as R, very particularly preferably H;
R ": as R, very particularly preferably methyl;
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: H; OH; Halogen or other usual leaving groups and their combinations; preferably Cl, Br, I, O-tosyl, methyl sulfonate, trifluoromethyl sulfonate, alkanoates and aryl carboxylates; particularly preferably H, Cl, Br;
X ': a leaving group, OH and / or halogen, preferably Cl, Br, I, O-tosyl, methyl sulfonate, trifluoromethyl sulfonate, alkanoates and / or aryl carboxylates, particularly preferably Cl, Br;
Y: S, NH, N-PG, NR, O, preferably NH, N-PG, NR, O, particularly preferably O;
Y ': H, OH, OR, O-PG, NH ₂ , NR ₂ , N (PG) ₂ , SR, SH, preferably O-PG and / or OR;
Y ": H, OH, OR, O-PG, NH ₂ , NR ₂ , N (PG) ₂ , SR, SH, Cl, Br, CR ' ₂ -EWG, preferably O-PG and / or OR, particularly preferably H or CH ₂ CO ₂ R or CH ₂ COR *;
Z: -OH, -O-PG, -OR, = O, = N-Nu, = CH-hetaryl, = CH-aryl, = PR ₃ ; where all of the aforementioned double-bonded groups Z are in (E) form, (Z) form or as an (E / Z) mixture, preferably = CH-hetaryl; particularly preferred = O, (E) - (2-methylthiazol-4-yl) -CH =, (E) - (2-methyloxazol-4-yl) -CH =;
Z ': O, OH, OR, O-PG, N (H) _1-2 , N (R) _1-2 , N (PG) _1-2 , SR, S-PG, R, preferably O, O- Is PG and / or OR;
Nu: R, O-PG, OR, N (PG) ₂ , NR ₂ , S-PG, SR, SeR, CN, N ₃ , aryl, heteroaryl, preferably R, O-PG, OR, N (PG) ₂ , NR ₂ , particularly preferably H, alkyl;
EEC: E and / or CN, CO-R, dialkylphosphonate, SO ₂ -R, SO ₂ OR, CF ₃ , CCl ₃ , NO ₂ ; preferably CN, CO-R, CO-NR particularly preferably CO ₂ R, CO ₂ PG, PG being very preferably tert-butyl;
Alkyl: hydrocarbons, also branched isomers, with C _1-20 , preferably 1-8 carbon atoms;
Aryl: phenyl, naphthyl, benzyl and their derivatives, preferably 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 / heteroaryl: 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 derivatives; and combinations thereof;
PG: protective group, preferably an allyl, methyl, t-butyl (preferably with EEC), benzyl, silyl, acyl or activated methylene derivatives such as methoxymethyl, alkoxyalkyl or 2-oxacycloalkyl protective group; preferred - predominantly for alcohol and amine functions -, trimethylsilyl, triethylsilyl, dimethyl-tert-butylsilyl, acetyl, propionyl, benzoyl, tetrahydropyranyl; furthermore suitable protective groups are those which simultaneously protect adjacent or divalent groups (PG ₂ ) with the formation of 5-7-membered rings, such as succinyl, phthalyl, methylene, acetonide; and / or combinations of all the aforementioned protective groups; is. 2. Structural element according to claim 1, wherein E = CH ₂ X, CO ₂ PG, preferably CHO. 3. Structural element according to claim 1 or 2, wherein EWG = H; X = H and / or halogen but is preferably Cl, Br, I. 4. Structural element according to one of the preceding claims, wherein the substituent Y-CO-CRR'X = OH, NH ₂ , preferably OH. 5. Structural elements according to one of the preceding claims with the general formula IV, preferably IVa, particularly preferably IVa with R = tert-butyl and X = H, Cl and / or Br. 6. Structural elements according to one of the preceding claims with the general formula V and / or Va according to one of the preceding claims, wherein
X ': a leaving group, OH and / or halogen, preferably Cl, Br, I, O-tosyl, methyl sulfonate, trifluoromethyl sulfonate, alkanoates and / or aryl carboxylates, particularly preferably Cl, Br;
Y ': H, OH, OR, O-PG, NH ₂ , NR ₂ , N (PG) ₂ , SR, SH, preferably O-PG and / or OR;
Z ': O, OH, OR, O-PG, N (H) _1-2 , N (R) _1-2 , N (PG) _1-2 , SR, S-PG, R, preferably O, O- Is PG and / or OR;
B ³ : single or double bond as E (trans) form, Z (cis) form or E / Z mixture; preferably single, double bonds to heteroatoms such as O, S, N, particularly preferably single bonds to O-PG and OH;
R: H, methyl, ethyl, propyl, phenyl, benzyl, preferably H, methyl, ethyl; or combinations thereof;
R ": as R, very particularly preferably methyl;
PG: protective group, preferably an allyl, methyl, t-butyl (preferably with EEC), benzyl, silyl, acyl or activated methylene derivatives such as methoxymethyl, alkoxyalkyl or 2-oxacycloalkyl protective group; preferred - predominantly for alcohol and amine functions -, trimethylsilyl-, triethylsilyl, dimethyl-tert-butylsilyl, acetyl, propionyl, benzoyl, tetrahydropyranyl; furthermore suitable protective groups are those which simultaneously protect adjacent or divalent groups (PG ₂ ) to form 5-7-membered rings, such as succinyl, phthalyl, methylene, ethylene, propylene, 2,2-dimethylpropa-1,3-diyl, acetonide ; and / or combinations of all the aforementioned protective groups; is. 7. Use of the structural elements with the general formula IV and / or IVa according to one of the preceding claims as a C1-C2 building block for epothilones and derivatives from that. 8. Use of the structural elements with the general formula IV and / or IVa according to one of the preceding claims as a C15-C16 building block for epothilones and derivatives from that. 9. Use of the structural elements with the general formula I according to one of the previous claims as a C7-C16 building block for the synthesis of epothilones and their Derivatives. 10. Use of the structural elements with the general formula V and / or Va according to one of the preceding claims as a C3-C6 building block for the synthesis of epothilone X and derivatives thereof, in particular by links in which compounds V and Va in compounds V with X '= M is transferred, where M = ZnX, MgX, Li, CrX ₂ , SmX ₂ , InX ₂ ; X is preferably halide, and these enolates with C-7 electrophilic building blocks, e.g. B. Type I with suitable substituents E, especially E = CHO. 11. Process for the synthesis of structural elements of the formula I according to one of the previous claims 1-6, 11, by reaction of in the α and / or ω position electrophilically activated prenyl compounds from 1-4 prenyl units with compounds according to the general formula IV. 12. A method for the synthesis of structural elements of the formula I according to any one of the preceding claims, wherein suitable prenyl compounds are selected from the group comprising prenyl alcohols, acetates, halides, compounds of the formula II, the formula III; and / or functionalized and / or protected prenyl derivatives of the general formula VIII,
wherein
B ¹ , B ² : single and 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;
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: H; OH; or halogen or other usual leaving groups and their combinations; preferably Cl, Br, I, O-tosyl, methyl sulfonate, trifluoromethyl sulfonate, alkanoates and aryl carboxylates; particularly preferably H, Cl, Br;
Nu: R, O-PG, OR, N (PG) ₂ , NR ₂ , S-PG, SR, SeR, CN, N ₃ , aryl, heteroaryl, preferably R, O-PG, OR, N (PG) ₂ , NR ₂ , particularly preferably H, alkyl;
R: H, alkyl, aryl, alkyl-aryl (CH ₂ aryl, C ₂ H ₄ aryl etc.), vinyl, 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, phenyl, benzyl, particularly preferably H, methyl, ethyl; or combinations thereof;
Alkyl: hydrocarbons, also branched isomers, with C _1-20 , preferably 1-8 carbon atoms;
Aryl: phenyl, naphthyl, benzyl and their derivatives, preferably 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;
PG: protective group, preferably an allyl, methyl, t-butyl (preferably with EEC), benzyl, silyl, acyl or activated methylene derivatives such as methoxymethyl, alkoxyalkyl or 2-oxacycloalkyl protective group; preferred - predominantly for alcohol and amine functions -, trimethylsilyl-, triethylsilyl, dimethyl-tert-butylsilyl, acetyl, propionyl, benzoyl, tetrahydropyranyl; protecting groups which protect adjacent or divalent groups (PG ₂ ) to form 5-7-membered rings simultaneously, such as succinyl, phthalyl, methylene, acetonide; and / or combinations of all the aforementioned protective groups;
wherein particularly preferably B ¹ = double bond; Nu = H; E = CH ₂ OH, CHO, CO ₂ R and / or X = Cl, Br, OTs. 13. Process for the synthesis of structural elements of the formula I according to one of the previous claims, wherein the prenyl compounds, preferably the Compounds of formulas II-III and / or VIII by means of C-C linkage nucleophilic substitution with 2-oxy-substituted-1,3-di-activated Methylene compounds of the formula IV, preferably 2-acyloxy-1,3-dicarbonyl compounds, particularly preferably with 2-acyloxy-acetoacetates, yet more preferably with compounds of the formula IVa, preferably in the presence of a or more bases, optionally with the addition of a solvent and / or in Presence of modifiers. 14. The method according to any one of the preceding claims, wherein the reaction temperature -80 ° C to + 180 ° C, preferably from -30 ° C to + 100 ° C, particularly preferably -5 ° C up to + 80 ° C.   15. The method according to any one of the preceding claims, wherein suitable bases are selected from the group comprising alkali metals, hydridic bases, Nitrogen bases in neutral or negatively charged form, alcoholates, hydroxides, Are carbonates, bicarbonates, and carbon ions; preferably hydridic Bases, nitrogen bases, negatively charged nitrogen bases, carbonates, bicarbonates; particularly preferably hydridic bases, carbonates and / or Hydroxides of alkali and alkaline earth metals such as NaH, KH, LiH. 16. The method according to any one of the preceding claims, wherein suitable solvents are selected from the group comprising hydrocarbons, alkanes, benzene and alkylated derivatives thereof, ether, dichloromethane, chloroform, Carbon tetrachloride, chlorinated aromatics, alcohols, ketones, sulfoxides, such as DMSO, Sulfolane, carboxamides, alkylated carboxamides, sulfolane, DMPU, Glymes, alkyl and aryl nitriles, carboxylic acid esters, tertiary amines and / or Mixtures thereof; preferably carboxamides and alkylated Carboxamides, ketones, sulfoxides (such as DMSO, sulfolane), alcohols, alkyl and / or aryl nitriles; particularly preferred carboxamides, alkylated Carboxamides, ketones, sulfoxides, DMSO, sulfolane, and / or alcohols. 17. Process for the synthesis of compounds I with EWG = H by alkyl decarboxylation or saponification / decarboxylation of compounds I with EWG = CO ₂ R or CO ₂ PG, preferably according to the Krapcho method, more preferably in the presence of LiCl and DMSO at elevated temperature , or particularly preferably starting from I with EWG = CO ₂ tBu in the presence of suitably strong acids, preferably volatile and anhydrous acids, particularly preferably trifluoroacetic acid. 18. A process for the synthesis of the compounds of general formula V according to of the preceding claims, wherein the compound of formula V with X '= H, preferably Va with Y '= OMe with a halogenating agent or an electrophilic Oxygen reagent in a suitable solvent to react, wherein optionally acidic or basic modifiers are added.   19. Compounds of the general formulas VI and VII according to one of the preceding claims, particularly suitable as a structural element for the synthesis of epothilones and derivatives thereof, with the general formula VI
with the general formula VII
wherein,
B ¹ : a single, double bond as E (trans) form, Z (cis) form or E / Z mixture; preferably single and double bonds;
R: H, alkyl, aryl, alkyl-aryl (CH ₂ aryl, C ₂ H ₄ aryl etc.), vinyl, 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, phenyl, benzyl, particularly preferably H, methyl, ethyl; or combinations thereof;
R ': as R, very particularly preferably H;
R ": as R, very particularly preferably methyl;
X ': OH; or halogen or other usual leaving groups and their combinations; preferably Cl, Br, I, O-tosyl, methyl sulfonate, trifluoromethyl sulfonate, alkanoates and aryl carboxylates; particularly preferably H, Cl, Br;
Y ': S, NH, NPG, NR, O, preferably NH, NPG, NR, O, particularly preferably O;
E: CH ₂ OH, CH ₂ OPG, CH ₂ OR, CH = O, CR = O, CH (OR) ₂ , CH (OPG) ₂ , CH = NPG, and combinations thereof; preferably COEt, CO ₂ R, COR *, CH (OPG) ₂ , particularly preferably CO ₂ R, CO ₂ PG, CO ₂ H, COR *;
R *: chiral residues and auxiliaries, in the case of acyl derivatives (esters, amides and imides) preferably 1-alkylbenzylamino or 1-alkylbenzyloxy, lactate and mandelate derivatives, monoterpene derivatives (e.g. Oppolzer-Sultam, 8-arylmenthyloxy etc.) or N -bound oxazolidinones (Evans-type auxiliaries), particularly preferably 4-substituted oxazolidinones, in each case in enantiomerically pure, enantiomerically enriched, racemic form, and / or mixtures thereof.
Alkyl: hydrocarbons, also branched isomers, with C _1-20 , preferably 1-8 carbon atoms;
Aryl: phenyl, naphthyl, benzyl and their derivatives, preferably 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;
PG: protective group, preferably an allyl, methyl, t-butyl (preferably with EEC), benzyl, silyl, acyl or activated methylene derivatives such as methoxymethyl, alkoxyalkyl or 2-oxacycloalkyl protective group; preferred - predominantly for alcohol and amine functions -, trimethylsilyl-, triethylsilyl, dimethyl-tert-butylsilyl, acetyl, propionyl, benzoyl, tetrahydropyranyl; protecting groups which protect adjacent or divalent groups (PG ₂ ) to form 5-7-membered rings simultaneously, such as succinyl, phthalyl, methylene, acetonide; and / or combinations of all the aforementioned protective groups;
in which very particularly preferred:
X '= Cl, Br; and R '= H; and R = Me and / or E = CO ₂ R, CO ₂ PG, CO ₂ H, COR * and B ¹ -Z '= O-PG; is. 20. A process for the synthesis of the compounds of general formula VI according to a of the preceding claims, wherein the compound of formula VII with a Halogenation agent or an electrophilic oxygen reagent in one suitable solvent to react and optionally acidic or add basic modifiers.   21. Process for the synthesis of the compounds with the general formula V and / or VI according to one of the preceding claims, wherein suitable halogenating reagents electrophilic halogenating agents, preferably elemental halogens, Halogenimide derivatives, sulfur (oxy) halides such as sulfuryl chloride, perhaloalkanes, and ammonium perhalides, particularly preferably tertiary or quaternary Ammonium perhalides such as pyridinium bromide perbromide, Trimethylphenylammonium bromide perbromide and / or polymer-bound variants of the aforementioned reagents. 22. A process for the synthesis of the compounds having the general formula V and / or VI according to one of the preceding claims, wherein the reaction temperature -80 to + 160 ° C, preferably -30 to + 65 ° C, particularly preferably -5 to + 10 ° C. 23. Process for the synthesis of the compounds with the general formula V and / or VI according to one of the preceding claims, wherein suitable solvents ethereal and halogenated solvents, preferably diethyl ether, THF, chloroform, Dichloromethane, liquid carboxamides and esters, preferably DMF, DMA, Ethyl acetate, liquid sulfoxides, preferably DMSO, sulfolane. 24. Structural elements with the general formula IXa and / or IXb according to one of the preceding claims, suitable as building blocks for the synthesis of polyketides, terpenoids, and / or epothilones and derivatives thereof, very particularly as C3-C16 building blocks for epothilones and derivatives thereof .
wherein
B ¹ , B ² , B ³ : single and 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 and B ³ as a single bond; and / or combinations thereof;
R: H, alkyl, aryl, alkyl-aryl (CH ₂ aryl, C ₂ H ₄ aryl etc.), vinyl, 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, phenyl, benzyl, particularly preferably H, methyl, ethyl; or combinations thereof;
R ': as R, very particularly preferably H;
R ": like R, very particularly preferably methyl
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: H; OH; or halogen or other usual leaving groups and their combinations; preferably H, Cl, Br, I, O-tosyl, methyl sulfonate, trifluoromethyl sulfonate, alkanoates and aryl carboxylates; particularly preferably Cl, Br;
Y: S, NH, N-PG, NR, O, preferably NH, N-PG, NR, O, particularly preferably O;
Y ': H, OH, OR, O-PG, NH ₂ , NR ₂ , N (PG) ₂ , SR, SH, preferably O-PG and / or OR;
Y ": H, OH, OR, O-PG, NH ₂ , NR ₂ , N (PG) ₂ , SR, SH, Cl, Br, CR ' ₂ -EWG, preferably O-PG and / or OR, particularly preferably Is H or CH ₂ CO ₂ R or CH ₂ COR *;
Nu: R, O-PG, OR, N (PG) ₂ , NR ₂ , S-PG, SR, SeR, CN, N ₃ , aryl, heteroaryl, preferably R, O-PG, OR, N (PG) ₂ , NR ₂ , particularly preferably H, alkyl;
Z: -OH, -O-PG, -OR, = O, = N-Nu, = CH-hetaryl, = CH-aryl, = PR ₃ ; where all of 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 =;
Z ': O, OH, OR, O-PG, N (H) _1-2 , N (R) _1-2 , N (PG) _1-2 , SR, S-PG, R, preferably O, O- Is PG and / or OR;
B ³ : single or double bond as E (trans) form, Z (cis) form or E / Z mixture; preferably single, double bonds to heteroatoms such as O, S, N, particularly preferably single bond to O-PG and double bond to O.
PG: protective group, preferably an allyl, methyl, t-butyl (preferably with EEC), benzyl, silyl, acyl or activated methylene derivatives such as methoxymethyl, alkoxyalkyl or 2-oxacycloalkyl protective group; preferred - predominantly for alcohol and amine functions -, trimethylsilyl-, triethylsilyl, dimethyl-tert-butylsilyl, acetyl, propionyl, benzoyl, tetrahydropyranyl; furthermore suitable protective groups are those which simultaneously protect adjacent or divalent groups (PG ₂ ) to form 5-7-membered rings, such as succinyl, phthalyl, methylene, ethylene, propylene, 2,2-dimethylpropa-1,3-diyl, acetonide ; and / or combinations of all the aforementioned protective groups;
EEC: E and / or H, CN, CO-R, dialkylphosphonate, SO ₂ -R, SO ₂ OR, CF ₃ , CCl ₃ , NO ₂ ; preferably CN, CO-R, CO-NR ₂ ; particularly preferably CO ₂ R, CO ₂ PG, PG being very preferably tert-butyl; and with X ≠ H also particularly preferably H;
Alkyl: hydrocarbons, also branched isomers, with C _1-20 , preferably 1-8 carbon atoms;
Aryl: phenyl, naphthyl, benzyl and their derivatives, preferably 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 / heteroaryl: 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 derivatives; and combinations thereof;
where particularly preferred
X ≠ H; and EWG = H; and Z = O, (E) - (2-methylthiazol-4-yl) -CH =, (E) - (2-methyloxazol-4-yl) -CH =; and R '= H, R "= Me; and / or Y" = CH ₂ COOH, OH; Y ', Z' = O-PG, OH; is. 25. A process for the synthesis of the structural elements IXa and / or IXb according to one of the preceding claims, in which the compounds I and V / Va; I and VI, or I and VII according to one of the preceding claims are converted into structural elements IX, preference being given to structural elements IX in which all carbon atoms of the macrocycle are present, particularly preferably in which the bonds C2-3 (such as IXa) and / or O15-C1 (e.g. IXa with Y-CO-CR ' ₂ X = OH or Y "= CH ₂ CO ₂ H), or C6-7 (as IXb) are still open and structural elements are more preferred Wear halogen at C2 and / or C6. 26. Process for the synthesis of the structural element IXa according to one of the previous ones Claims in which a C6-C7 linkage of compounds of formula I with those of the formula V, VI and / or VII, particularly preferably V, VI with X '= Cl, Br or I, in the presence of bases and / or in the presence of one or more metals and / or metal salts, optionally with the addition of solvents, catalysts and / or modifiers. 27. Process for the synthesis of the structural element IXa according to one of the preceding Claims, wherein the reaction temperature -80 ° C to + 140 ° C, preferably above 0 ° to 65 ° C, particularly preferably from 15 ° C to 35 ° C. 28. Process for the synthesis of the structural element IXa according to one of the previous ones Claims, suitable metals, preferably Li, Mg, Zn, In, Mn, Fe, also in activated form; suitable metal salts, preferably inorganic or organic Salts and / or complexes or organometallic compounds of the metal ions Ti (II), Ti (III), Cr (II), Sm (II), Co (I), V (II) and Fe (II), especially as halide, sulfate, Sulfonate, alkanoate, cyclopentadienylate and phenylate, or solid phase or polymer-bound; also in combinations; zinc, titanium (II) are particularly preferred or very particularly preferably a Cr (II) compound as chloride, bromide, acetate, Sulfate, generated in situ or polymer bound. 29. A method for the synthesis of the structural element IXa according to any one of the preceding claims, wherein suitable catalysts iodides; non-reducible Lewis acids, e.g. B. lithium salts, aluminum chloride, boron trifluoride, which also arise in situ in the formation of reducing metal salts with LiAlH ₄ ; Nickel (II) salts and nucleophilic, redox-active metal complexes, e.g. B. Vitamin B12 and comparable synthetic co-complexes, preferably in amidic solvents and sulfolane; comprise, preferably up to 33 mol% of the anhydrous catalyst, preferably 0.01-5 mol%; reactive Lewis acids optionally mixed with the solid, low-valent salt, preferably mixed before the addition of the solvent. 30. Process for the synthesis of the structural element IXa according to one of the preceding Claims wherein modifiers are iodides (MI), non-reducible common ones Lewis acids, e.g. B. lithium salts, aluminum chloride, boron trifluoride; complexing Ligands, especially chiral ones, especially bidentates, and other common ones usable ligands; as well as combinations of all the additives mentioned, preferably in the anhydrous state; particularly preferred anhydrous lithium iodide, sodium iodide and aluminum chloride. 31. Process for the synthesis of the structural element IXa according to one of the previous ones Claims, suitable solvents hydrocarbons (alkanes, benzene and alkylated derivatives), ether, dichloromethane, chloroform, chlorinated aromatics, sec./tert.- alcohols, ketones, dimethyl sulfoxide (DMSO), carboxamides and alkylated Carboxamides, sulfolane, DMPU, glymes, alkyl and aryl nitriles, Carboxylic acid esters, tertiary amines and mixtures thereof, but preferably Methyl tert-butyl ether, diethyl ether, tetrahydrofuran, glymes, sulfolane, DMSO, Ketones up to C5, dimethylformamide and acetamide or acetonitrile or mixtures from that; solvents which are as anhydrous as possible are particularly preferred. 32. Process for the synthesis of the structural element IXa according to one of the preceding Claims in which one or more metal salts by reduction with one Reducing agent is converted into an oxidation stage that can be used for the process becomes; this reaction preferably in situ or, if appropriate, the actual one Reaction is carried out beforehand. 33. Process for the synthesis of the structural element IXa according to one of the preceding Claims, with suitable reducing agents / processes preferred electrochemical processes, lithium aluminum hydride and comparable hydrides, metallic iron or manganese in their various forms, especially preferably include lithium aluminum hydride and zinc.   34. Process for the synthesis of the structural element IXb according to one of the preceding Claims in which an O15-C1 linkage of compounds of the formula I with those of the formula VI or VII, particularly preferably VI with X '= Cl, Br or I, in Presence of esterification, transesterification catalysts, and / or Coupling reagents, optionally with the addition of solvents. 35. Process for the synthesis of the structural element IXb according to one of the preceding Claims, wherein the reaction temperature -50 ° C to + 160 ° C, preferably above 0 ° to 100 ° C, particularly preferably from 15 ° C to 55 ° C. 36. Process for the synthesis of the structural element IXb according to one of the preceding Claims, wherein esterification and / or transesterification catalysts, for this Purposes include conventional bases, acids, metal alcoholates such as titanium tetraalcoholates, whereby for the esterification of free acids, preferably coupling reagents, preferably selected from the group comprising EDCI, DCC / DMAP and / or Methods such as Yamaguchi esterification can be used. 37. Process for the synthesis of the structural element IXb according to one of the preceding Claims, suitable solvents hydrocarbons (alkanes, benzene and alkylated derivatives), ether, dichloromethane, chloroform, chlorinated aromatics, Carboxamides, alkylated carboxamides, sulfolane, DMPU, Glymes, alkyl and aryl nitriles, carboxylic acid esters, tertiary amines and mixtures thereof, but preferably water-free solvents, methyl tert-butyl ether, Diethyl ether, tetrahydrofuran, glymes, sulfolane, chloroform, dichloromethane and / or mixtures thereof; particularly preferably chloroform, and / or Include dichloromethane. 38. A process for the synthesis of a compound of formula I with E ≠ CH ₃ , characterized in that a protected compound of formula 1 (E = CH ₃ ), preferably Ia (E = CH ₃ ), is oxidized in the allyl position and / or is present functional groups oxidized. 39. A method for synthesizing a compound according to claim 29, wherein selenium dioxide as an oxidizing agent, preferably catalytically.   40. Process for the synthesis of a compound of formula I and / or formula IX, thereby characterized in that one or more double bonds of a protected or modified compound of the formula I and / or of compounds of the formula IX, a nucleophile or electrophile added, reduced, epoxidized or cyclopropanated, preferably the C8-C9 double bond is reduced and / or the C12-C13 Epoxidized double bond and / or added a nucleophile at C9; most notably a C8-C9 double bond is preferably asymmetrically, catalytically hydrogenated; and / or combinations thereof. 41. Process for the synthesis of epothilone macrocycles and derivatives having the formula X below
wherein:
B ¹ , B ² , B ³ : single and 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 and B ³ as a single bond; and / or combinations thereof;
R: H, alkyl, aryl, alkyl-aryl (CH ₂ aryl, C ₂ H ₄ aryl etc.), vinyl, 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, phenyl, benzyl, particularly preferably H, methyl, ethyl; or combinations thereof;
R ': as R, very particularly preferably H
R ": like R, very particularly preferably methyl
Y: S, NH, N-PG, NR, O, preferably NH, N-PG, NR, O, particularly preferably O;
Y ': H, OH, OR, O-PG, NH ₂ , NR ₂ , N (PG) ₂ , SR, SH, preferably O-PG and / or OH;
Nu: R, O-PG, OR, N (PG) ₂ , NR ₂ , S-PG, SR, SeR, CN, N ₃ , aryl, heteroaryl, preferably R, O-PG, OR, N (PG) ₂ , NR ₂ , particularly preferably H
Z: -OH, -O-PG, -OR, = O, = N-Nu, = CH-hetaryl, = CH-aryl, = PR ₃ ; where all of 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 =;
Z ': O, OH, OR, O-PG, N (H) _1-2 , N (R) _1-2 , N (PG) _1-2 , SR, S-PG, R, preferably O, O- Is PG and / or OR;
B ³ : single or double bond as E (trans) form, Z (cis) form or E / Z mixture; preferably single, double bonds to heteroatoms such as O, S, N, particularly preferably single bond to O-PG and OH.
PG: protective group, preferably an allyl, methyl, t-butyl (preferably with EEC), benzyl, silyl, acyl or activated methylene derivatives such as methoxymethyl, alkoxyalkyl or 2-oxacycloalkyl protective group; preferred - predominantly for alcohol and amine functions -, trimethylsilyl-, triethylsilyl, dimethyl-tert-butylsilyl, acetyl, propionyl, benzoyl, tetrahydropyranyl; furthermore suitable protective groups are those which simultaneously protect adjacent or divalent groups (PG ₂ ) to form 5-7-membered rings, such as succinyl, phthalyl, methylene, ethylene, propylene, 2,2-dimethylpropa-1,3-diyl, acetonide ; and / or combinations of all of the aforementioned protective groups.
Alkyl: hydrocarbons, also branched isomers, with C _1-20 , preferably 1-8 carbon atoms;
Aryl: phenyl, naphthyl, benzyl and their derivatives, preferably 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 / heteroaryl: 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 derivatives; and combinations thereof;
where particularly preferred
Z = O, (E) - (2-methylthiazol-4-yl) -CH =, (E) - (2-methyloxazol-4-yl) -CH =; and R '= H, R "= Me; Y', Z '= O-PG, OH, Y = O
by ring-closing lactonization or Reformatsky-type reactions or macroaldolizations of the open-chain compound of the formula IX, with links to C2-C3 and C6-C7 and EWG = H being preferred, particularly preferably starting from compounds IX with X = Cl, Br, I with Chromium (II) salt, indium or zinc. 42. Process for the synthesis of compounds of formula I, IV, IVa, V, Va, VI; VII, VIII, IXa, IXb and / or X, the process steps for the synthesis of the respective Compounds of the formulas I to X are repeated in any meaningful order and / or combined, wherein between the combined steps and / or Repetitions protecting groups removed, modified and / or appropriately can be introduced.