WO1998008849A1

WO1998008849A1 - Method for producing epothilones, and intermediate products obtained during the production process

Info

Publication number: WO1998008849A1
Application number: PCT/DE1997/000111
Authority: WO
Inventors: Dieter Schinzer; Anja Limberg; Oliver M. BÖHM; Armin Bauer; Martin Cordes
Original assignee: Novartis Aktiengesellschaft
Priority date: 1996-08-30
Filing date: 1997-01-15
Publication date: 1998-03-05
Also published as: EP0923583A1; AU2149397A; AU716610B2; NZ334821A; JP2001500851A

Abstract

The invention pertains to a method for producing epothilones and also relates to intermediate products obtained during the production process. Epothinone A and B are natural substances which can be produced by microorganisms and have similar properties to those of taxol and, therefore, are of interest to the pharmaceutical chemistry.

Description

Process for the production of epothilones and intermediates within the process

The invention relates to processes for the production of epothilones and intermediates within the process.

Epothilone 1 (DE 41 38 042 C2) represent a new class of tubulin-stabilizing natural products with T.axol-like activity. Their cytotoxic activity against drug-resistant tumor cell lines is of enormous importance for potential use in cancer therapy [G. Höfle , N. Bedorf, H. Steinmetz, D. Schomburg, K. Gerth, H. Reichenbach Angew. Chem. 1996, 108, 1671; Appl. Chem. Int. Ed. Engl. 1996, 35, 1567; D. Schinzer "Epothiiones - New Promising Microtubule-stabilizing Natural Products with Taxol-like Biological Activity", Eur. Chem. Chron. 1996, 1, 7; D.M. Bollag, P.A. McQueney, J. Zhu, O. Heπsens, L. Koupal, J. Liesch, M. Goetz, E. Lazarides, C.M. Woods, Cancer Res. 1995, 55, 2325].

Epothilones 1 (A: R = H, B: R = Me) have recently been isolated from myxobacteria and are accessible via fermentation. Due to the very interesting biological properties, the synthesis of the epothilones is of the greatest importance. The invention relates to the total synthesis of epothilones A and B1.

ERSATZB.LATT (RULE 26)

Scheme 1 Retrosynthetic analysis,

[D. Schinzer, A ümberg O M Böhm, Chem. Eur J 1996, 2, 1477]

Epothilones 1 are accessible in a convergent reaction from the three building blocks 2, 3 and 4. As the retrosynthesis in Scheme 1 shows, building blocks 2 and 3 are linked in a stereoselective aldol reaction. Esterification with fragment 4 provides the almost fully functionalized fragment 17, which is in A cyclization metathesis to deoxy-epothilone A 19 is cyclized. A final epoxidation finally provides 1 The key step in the synthesis is the stereoselective aldol reaction of fragments 2 and 3 (obtainable from the commercially available heptenic acid). Under kinetically controlled reaction conditions in the presence of LDA, 70 is obtained % Yield exclusively the desired compound 5 with the four correctly placed asymmetry centers. Double stereodifferentiation obviously leads to a chiral override of the preferred Cra selectivity of the aldehyde 3, since both reactants are optically active Form are used

ERSATZBI_ATT (RULE 26) The invention thus relates to a process for the preparation of epitholone A or B of the general formula 1

wherein R = hydrogen (A) or a methyl group (B), a thiazole alkyl dieπ alcohol derivative of the formula 4th

OH

with a carboxylic acid of the general formula 9a

where B = benzyl, tetrahydropyranyl and / or a silyl protecting group (s) and

R = hydrogen or methyl, is esterified, the ester obtained is ring-closed by means of an open metathesis in the presence of a noble metal catalyst, optionally the hydroxyl protective groups

REPLACEMENT BI ATT (RULE 26) are cleaved, the newly formed double bond is epoxidized and, if necessary, the hydroxyl protective groups are cleaved.

Suitable as silyl protective groups B are generally all different trialkyl or diaryl-alkyl silyl protective groups, in particular the tert-butyl-diethyl, trimethylsilyl and diphenyl-tert-butyl-silyl groups.

The derivatives 4a and 9a are esterified, preferably by using DCCI / DMAP, and the ester thus obtained with the two terminal alkene groups is ring-closed by opening metathesis, preferably by using RuCI ₂ (= CHPh) (PCy ₃ ) 2 (Grubbs catalyst) (J. Org. Chem. 1996, 61, 3942 - 3943; Tetrahedron 1996, 52, 7251 - 7264; J. Am. Chem. Soc., 1995, 117, 12364 - 12365; J. Am. Chem. Soc., 1995, 117, 2943 - 2944 and Tetrahedron Lett .; 1994, 35, 3191 - 3194, J. Am. Chem. Soc., 1996, 118, 6634 - 6640 and J. Am. Chem. Soc., 1995, 118, 100-110.

The epoxidation of the newly formed double bond is preferably carried out using peracid, e.g. B. perchloric acid, or peroxide, e.g. B. cumene hydroperoxide or dimethyldioxirane.

The invention further includes deoxy-epothilones according to general formula 19a

where B = hydrogen, benzyl, p-methoxybenzyl, tetrahydropyranyl and / or a silyl protecting group (s) and R = hydrogen or methyl, (2- (2,2-dimethyl- [1, 3] dioxane-4- yl) -2-methyl-pentan-3-one) 2,2-methyl-6-heptenal 3

H

and 2,6-dimethyl-6-heptenai 3a,

and compounds of general formula 9a

wherein B = benzyl, tetrahydropyranyl and / or a silyl protective group (π) and

R = hydrogen or methyl, and the meaning of B in the molecule can be different, and compounds of the general formula 4a

4a

OB in what

B = hydrogen, benzyl, p-methoxybenzyl, tetrahydropyranyl or a silyl protecting group and (4S, 6S) -2- (2,2-dimethyl- [1, 3] dioxan-4-yl) -5-hydroxy-

REPLACEMENT BL. ATT (RULE 26) as well as stereoisomers of the claimed compounds.

8th

Scheme 2. a) LDA, THF, - 78 ° C, 70%; b) pyridinium p-toluenesulfonate (PPTS), MeOH, RT, 36 h, 88%; c) 12 eq. / BuMe2SiOTf (Tf = trifluoromethanesulfonate), 6 eq. 2,6-lutidine, CH 2 Cl 2 - 78 ° C, 96%; d) 0.2 eq. CSA (camphorsulfonic acid), MeOH, CH2Cl2, 0 ° C, 5 h, 82%; e) 1 eq. Pyridinium dichromate (PDC), DMF, RT, 36 h, 79%.

The cleavage of the acetonide 5 to the triol 6 succeeds smoothly in the presence of pyridinium p-toluenesulfonate (PPTS). Subsequent trisilylation with TBSOTf and lutidine as auxiliary base provides the desired compound 7. In order to enable oxidation to acid 9, the primary silyl group must be selectively removed. This succeeds smoothly in the presence of camphorsulfonic acid (CSA) and generates compound 8. A final oxidation with pyridinium dichromate (PDC) produces fragment 9, which is the C1-C12 subunit of 1.

10 11 12

15

Scheme 3. a) TBSCI, imidazole, DMF, RT, 10 h, 98%; b) O3, PPh3, CH2CI2, - 78 ° C, 70%; c) 1.5 eq. Diethyl (2-methylthiazol-4-yl) methane phosphonate, πBuLi, THF, - 78 ° C -> RT, 75%; d) HF, MeCN, some glass fragments, 0 ° C, 87%; e) Dess-Martin Periodinaπ, CH2CI2, RT, 1 h, 78%; f) 1.85 eq. PPh3MeBr / NaNH2, THF, RT, 20 min, 83%; g) 2.5 eq. Tetrabuty.ammonium fluoride (TBAF), molecular sieve 4 A, THF, - 78 ° C -> RT, 99%.

The (S) alcohol 10 [D. Schinzer, A. Limberg, OM Böhm, Chem. Eur. J. 1996, 2, 1477] was first silylated with TBSCI, then ozonized to methyl ketone 12 and converted to the tricyclic olefin 13 in a stereoselective Horner-Wadsworth-Emmons reactionΛ A selective desilylation with HF in acetonitrile gives compound 14. The desilylation to 14 only works in the presence of some glass splinters; the reaction is apparently catalyzed by H2SiF6. Dess-Martin oxidation followed by a Wittig

ERSATZB.LATT (RULE 26) Olefination generates compound 16, which in a final desilylation with TBAF in THF segment 4 yields.

Esterification of building blocks 9 and 4 in the presence of DCC and 4-DMAP produces compound 17, which is isolated in stereochemically homogeneous form.

Epothilon C: 19

Scheme 4. a) 1.3 eq. Dicyclohexylcarbodiimide (DCC), 0.2 eq. 4-dimethylaminopyridine (4-DMAP), CH2Cl2, RT, 12 h, 80%; b) Cl2 [RuCHPh] (PCy3) 2, CH2CI2, RT, 12 h, 94% {Z: E = 1: 1); c) HF, MeCN, E.2O, RT, 12 h, 65%, d) dimethyldioxirane, CH2CI2, - 35 ° C, 2 h, 48%. Ring closure metathesis with Cl2 [RuCHPh] (PCy3) 2 in CH2CI2 gives 18 as a mixture of diastereomers (Z: E = 1: 1) in 94% yield. The total synthesis is completed by desilylation with HF in acetonithl / ether to 19 and regio- and stereoselective epoxidation with dimethyldioxirane to 1. The main product of this reaction is (-) - epothilone A, which is identical to an authentic sample by chromatography and spectroscopy.

Overall, a strictly convergent synthesis has been described that offers many options for analogues, which is important in terms of biological activity. The entire synthesis comes with one type of protective group (TBS), which are linked or split off in selective reactions. The stereoselective aldol reaction is high and is another impressive example of the chiral override of the aldehyde selectivity with a chiral enolate. The ring-closing metathesis to 18 succeeds in 94% isolated yield, but provides a 1: 1 mixture of the Z and E isomers. The biologically significantly more effective epothilone B 1 (R = Me) can be obtained via the same production route.

11

Production of 2nd

Working instructions for the synthesis of segment 2

(2- (2,2-dimethyl- [1,3] dioxan-4-yl) -2-methylpentan-3-one) p. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477].

The 3 - [(terf-butyldimethylsilyl) oxy] propanal 42 is prepared starting from propane-1,3-diol 40 by first using a method of P.G. McDougal, J.G. Rico, Y. Oh, B.D. Condon, J. Org. Chem. 1986, 51, 3388-3390, is monosilylated to 3 - [(tert-butyldimethylsilyl) oxy] -1-propanol 41, which is then oxidized with DMSO / oxalyichloride to form aldehyde 42 (A. Jenmalm , W. Berts, Y. Li, K. Luthmann, I. Csöregh, U. Hacksell, J. Org. Chem. 1994, 59, 1139-1148).

Preparation of 1 - [(fert-butyldimethylsilyl) oxy] -4,4-dimethyl-hex-5-en-3-ol 43

(H.C. Brown, P.K. Jadhav, Tetrahedron Lett. 1984, 25, 1215-1218; P.K. Jadhav, K.S. Bhat and P. Thirumalai, H.C. Brown, J. Org. Chem. 1986, 51, 432-439)

To a suspension of lpc2BH (7.34 mmol, prepared from (-) - -pinene [99%, 97% ee]) cooled to -25 ° C. HC Brown, MC Desai, PK Jadhav, J. Org. Chem. 1982, 47, 5065-5069; HC Brown, B. Singaram, J. Org. Chem. 1984, 49, 945-947) in 2.6 ml THF, 500 mg (7.34 mmol, 1 equiv) 3-methyl-1, 2-butadiene is slowly added dropwise and the reaction mixture was stirred at -25 ° C. for 6 h. The THF is then pumped off at RT (14 mm Hg / 1 h), (0.5 mm / 2 h) and the residue is dissolved in 10.5 ml of diethyl ether. The solution is cooled to -78 ° C. and 1,382 g (7.34 mmol, 1 equiv) aldehyde 42 are added dropwise. The mixture is stirred for 12 h at -78 ° C. and then allowed to warm to RT. The reaction mixture is mixed with 10.7 ml of 3N NaOH solution, then with 4.4 ml of 30% H2O2 solution and heated under reflux for 2 h. The organic phase is separated off, saturated with 15 ml of H2O and 15 ml. Washed NaCl solution, dried over MgSO4 and concentrated. The residue is purified by column chromatography with pentane: ether = 2: 1 and 800 mg (3,098 mmol) of alcohol 43 are obtained, corresponding to a yield of 42%. The enantiomeric excess was determined by GC analysis of the diastereomeric compounds which are obtained by esterifying the alcohol with (1 R) - (-) - camphanoyl chloride and gave an ee value of 92%.

General data: C- ^ HaoC ^ Si, FG = 258.47 g / mol ³ C-NMR (100 MHz, CDCI ₃ ): 145.69 (d), 112.27 (t), 78.52 (d), 63.29 (t), 41.19 (s), 33.39 (t), 25.89 (q), 22.85 (q ), 22.43 (q), 18.17 (s), -5.52 (q)

Preparation of 4- (1, 1-dimethyl-allyl) -2,2-dimethyl- [1,3] dioxane 44

278 mg (1,076 mmol) of alcohol 43 are dissolved in 13 ml of acetone and 200 mg (2.51 mmol, 2.3 eqiuv) of anhydrous CUSO4 are added. Then 40 drops of a solution of 0.1 ml glacial acetic acid in 1 ml CH2Cl2 are added dropwise and the mixture is stirred at RT for 12 h. If starting material can still be detected by TLC, further acid solution is added until the reaction is complete. For working up, the reaction mixture is saturated. Poured NaHCO 3 solution and extracted the aqueous phase with DE. The combined organic phases are dried over MgSO.4 and concentrated on a rotary evaporator. The residue is purified by column chromatography with pentane: ether = 2: 1. 161 mg (0.87 mmol) of acetonide 44 are obtained, corresponding to a yield of 81%.

General data: C11 H20O2. ^FG = 184.28 g / mol

1 ³ C-NMR (100 MHz, CDCl3): 145.10 (d), 111.88 (t), 98.19 (s), 75.32 (d), 60.10 (t),

39.97 (s), 29.80 (q), 25.88 (t), 22.86 (q), 22.45 (q), 19.11 (q)

Preparation of 2- (2,2-dimethyl- [1,3] dioxan-4-yl) -2-methyl-propionaldehyde 45

286 mg (1.55 mmol) of the acetonide 44 are dissolved in 18 ml of THF and 14 ml of aqueous phosphate buffer pH 7 are added. 400 μl (0.031 mmol, 0.02 equiv) OsO4 solution (2.5% in terf-butanol) is added dropwise to the vigorously stirred reaction mixture. After 10 minutes, 996 mg (4,656 mmol, 3 equiv) of NalO4 are added in portions over a period of 20 minutes. The mixture is stirred vigorously at RT and, after 24 and 48 h, a further 332 mg (1.55 mmol, 2x1.0 equiv) of NalO4 are added. After 55 h the phases are separated, the aqueous phase is extracted with ether, the combined organic phases are dried over gSO 4 and concentrated. The residue is purified by column chromatography with PentamDE = 1: 1. 221 mg (1.19 mmol) of aldehyde 45 are obtained, corresponding to a yield of 76%.

REPLACEMENT BOOK (RULE 26) General data: CιoH- | 8 ⁰ 3. FG = 186.25 g / mol

^" • ³ C-NMR (100 MHz, CDCI ₃ ): 206.09 (d), 98.43 (s), 72.94 (d), 59.75 (t), 48.84 (s),

29.57 (q), 25.57 (t), 18.96 (q), 18.62 (q), 16.46 (q)

Preparation of 2- (2,2-dimethyl- [1,3] dioxan-4-yI) -2-methyl-pentan-3-ol -46

A solution of 268 mg (1.44 mmol) of the aldehyde 45 in 4 ml of diethyl ether is mixed at 0 ° C. with 528 μl (1.58 mmol, 1.1 equiv) of a 3 M solution of EtMgBr in ether. The mixture is stirred at 0 ° C. for 2 h, warmed to RT and left to stir for a further hour. For working up with sat. aqueous NH4CI solution was added and then enough water was added until the precipitate dissolved. The aqueous phase is extracted with ether, the combined organic phases are dried over MgSO4 and concentrated. The residue is purified by column chromatography with pentane: ether = 1: 1. 251 mg (1.16 mmol) of alcohol 46 are obtained, corresponding to a yield of 80%.

General data: C12H24O3, FG = 216.31 g / mol

¹³ C-NMR (100 MHz, C ₆ D ₆ ): 98.41 (s), 79.95 (d), 76.65 (d), 60.10 (t), 40.60 (s),

Diastereomer 1: 30.04 (q), 25.73 (t), 24.64 (t), 20.03 (q), 19.25 (q), 15.99 (q), 11.67

(q)

¹³ C-NMR (100 MHz, C ₆ D ₆ ): 98.57 (s), 78.85 (d), 76.46 (d), 60.08 (t), 39.93 (s),

Diastereomer 2: 30.02 (q), 25.41 (t), 25.08 (t), 20.85 (q), 20.30 (q), 18.90 (q), 11.95

(q)

Preparation of 2- (2,2-dimethyl- [1,3] dioxan-4-yl) -2-methylpentan-3-one 2:

W.P. Griffith, S.V. Ley, G.P. Whitcombe, A.D. White, J. Chem. Soc, Chem. Commun. 1987, 1625-1627

70 mg (0.32 mmol) of the alcohol 46 are dissolved in 5 ml of CH2Cl2 and 6 4 Å molecular sieve balls and 66 mg (0.48 mmol, 1.5 equiv) 4-methylmorpholine N-oxide (NMO) are added. After stirring for 10 minutes, 6 mg of tetrapropylammonium perruthenoate (VII) (TPAP) (0.016 mmol, 0.05 equiv) are added and the mixture is stirred at RT for 4 h. The reaction mixture is then concentrated on a rotary evaporator and directly purified by column chromatography with pentane: ether = 1: 1. 60 mg (0.28 mmol) of ethyl ketone 2 are obtained, corresponding to a yield of 86%. General data: C12H22O3, FG = 214.30 g / mol

¹ 3 <S-NMR (100 MHz, C ₆ D ₆ ): 213.23 (s), 98.42 (s), 74.18 (d), 59.82 (t), 50.44 (s),

31.70 (t), 30.03 (q), 25.55 (t), 20.97 (q), 19.35 (q), 19.04 (q), 8.16 (q)

Synthesis of 2-methyl-6-heptenal 3 and 3a

The preparation is based on the synthesis of 6-tert-butyldimethylsilyloxy-2-methyl-hexanal 50 [D. Schinzer, A. Limberg, 0. M. Böhm, Chem. Eur. J. 1996, 2, 1477].

ERSATZB.LATT (RULE 26)

Working instructions for the presentation of segment 3:

The sodium 6-hydroxyhexanoate is produced according to a regulation by Wulff, Krüger and Röhle Chem. Ber. 1971, 704, 1387-1399 made from ω-caprolactone.

Preparation of 6 - [(tert-butyldimethyisilyl) oxy] hexanoic acid silyl ester

A mixture of 2.00 g (12.97 mmol) of sodium 6-hydroxyhexanoate, 25 ml DMF, 5.87 g (38.93 mmol, 3 equiv) TBDMSCI and 5.3 g (77.85 mmol, 6 equiv) imidazole is stirred for 48 hours at RT. The reaction mixture is flash filtered and then purified by column chromatography with pentane: DE = 4: 1. 3.99 g (11.1 mmol) of the bissilylated compound 6 - [(terf-butyldimethylsilyl) oxy] -hexanoate, corresponding to a yield of 85% .

General data: C- | 8H4θθ3Si2, FG = 360.69 g / mol

¹³ C-NMR (100 MHz, CDCI3): 174.17 (s), 63.00 (t), 36.02 (t), 32.53 (t), 25.95 (q),

25.55 (q), 25.40 (t), 24.91 (t), 18.33 (s), 17.57 (s), -4.83 (q), -5.32 (q)

Preparation of 6 - [(ferf-butylimethylsilyl) oxy] hexanoic acid according to DR Morton, JL Thompson, J. Org. Chem. 1978, 43, 2102-2106. A solution of 3.25 g (9.02 mmol) of the bissilylated compound 6 - [(te / τ-butyldimethylsilyl) oxy] -hexanoic acid silyl ester in 130 ml of methanol and 44 ml of THF is mixed with a solution of 4.4 g (31.8 mmol, 3.5 equiv) K2CO3 in 44 ml of H2O and stirred at RT for 1 h. The volume of the reaction solution is then reduced to a quarter in vacuo. It is diluted with 130 ml of sat. NaCI solution and adjust to pH 4-5 with 1 M KHS04 solution. It is extracted with diethyl ether. The combined organic phases are dried over MgSO4 and the solvent is distilled off on a rotary evaporator. This gives 2.01 g (8.17 mmol) of 6 - [(terr-rutvlriimethvlsilvhoxvl-hexanoic acid, corresponding to a yield of 90%. General data: C- | 2H26θ3Si, FG = 246.42 g / mol

^" I3C-NMR (100 MHz, CDCI ₃ ): 180.09 (s), 62.90 (t), 34.05 (t), 32.37 (t), 25.93 (q),

25.31 (t), 24.46 (t), 18.32 (s), -5.33 (q)

Preparation of 6 - [(fert-butyldimethylsilyl) oxy] hexanoyl chloride

J. Tanaka, Bull. Chem. Jpn. 1992, 65, 2851-2853.

A solution of 0.5 g (2.03 mmol) of 6 - [(tert-butyldimethylsilyl) oxy] -hexanoic acid in 4 ml of benzene is mixed with 362 mg (3.04 mmol, 1.5 equiv) of SOCI2 and heated under reflux for 2 h. The mixture is allowed to cool and the solvent is distilled off on a rotary evaporator. In order to remove the excess SOCI2 from the reaction mixture, the residue is mixed again with benzene and distilled off again. 494 mg (1,865 mmol, 92%) of the 6 - [(tert-butyldimethylsilyl) oxy] hexanoyl chloride are obtained. This raw product is further implemented without purification and characterization.

* (.S) -4-isopropyl-3-propenoyl-oxazolidin-2-one 20

Illustration based on: D. A. Evans, K. T. Chapman, J. Bisha J. Am. Chem. Soc. 1988, 110, 1238; A. Studer, T. Hintermann, D. Seebach Helv. Chim. Acta 1995, 78, 1185. To a solution of 1, 299 g (10.0 mmol) (S) -4-isopropyl-oxazolidin-2-one in 15 ml of absolute THF, 6.88 ml of a 1 , 6M solution of n-BuLi in hexane (11.0 mmol). The solution is stirred for 30 min at -78 ° C., 1.22 ml (15.0 mmol) of acrylic acid chloride are added dropwise, the mixture is brought to room temperature and hydrolyzed with 50 ml of saturated NH4Cl solution. It is extracted three times with 50 ml Et2θ each. After drying over MgSO.4, the solvent is removed. Flash chromatographic purification with pentane / Et2θ (10: 1) gives 1.63 g (8.9 mmol, 89%) £ 0 •

ERSATZBI.ATT (RULE 26) (S) -4-isopropyl-3- (6-methylhept-6-enoyl) oxazolldin-2-one 21a

Representation based on:

A. Studer, T. Hintermann, D. Seebach Helv. Chim. Acta 1995, 78, 1185 47 mg (1.9 mmol) Mg turnings are at room temperature (or with occasional warming) in 1.5 ml absolute THF with 283 mg (1.9 mmol) 4-bromo-2-methyl-1-butene stirred until all the Mg has dissolved. A suspension of 197 mg (1.00 mmol) of CuBr-Me2S in 1.5 ml of absolute THF is added to this Grignard solution at -30 ° C. Stirring 30 mm at this temperature gives 117 mg (0.64 mmol) of 20 in 2 ml add absolute THF, stir for 16 h at -10 ° C and hydrolyze with 10 ml saturated NH4CI solution. It is extracted three times with 20 ml Et2θ each. After drying over MgSO 4, the solvent is removed. Flash chromatographic purification with pentane / Et 2 O (15 1) gives 128 mg (0.51 mmol, 79%) 21a

Hept-6-enoyl chloride

A solution of 2.58 g (20 13 mmol) hept-6-enoic acid in 10 ml CH2Cl2 is mixed with 5.11 g (40.26 mmol, 2 eq) oxalyl chloride, then stirred for 1 h at RT and 1 h at 40 ° C. The mixture is allowed to cool and the solvent is distilled off at 5 mbar. 2.95 g (20.13 mmol, 100%) of the acid chloride are obtained. This crude product is reacted without further purification.

General data: C7H11 CIO, FG = 146.62 g / mol (S) -3-hept-6-enoyl- -isopropyl-oxazolidin-2-one ^

A. Gonzalez, Synth. Comm. 1991, 21, 1353-1360

A solution of 2.08 g (16.10 mmol, 1 eq.) (4S) -4-isopropyl-oxazolidin-2-one in 15 ml THF is cooled to -78 ° C and added dropwise with 11.6 ml (18.52 mmol, 1.15 eq.) a 1.6 M solution of n-BuLi solution in hexane. A solution of 2.95 g (20.13 mmol, 1.25 eq.) Of hept-6-enoyl chloride in 10 ml of THF is then added at -78 ° C. The mixture is allowed to warm to RT and the reaction solution is poured onto saturated NaCl solution. The aqueous phase is extracted with ether, the combined organic phases are dried over MgSO 4 and the solvent is distilled off on a rotary evaporator. The residue is purified by column chromatography using PE: DE = 3: 1. 3.55 g (14.82 mmol, 92%) of oxazolidinone 21 are obtained as a colorless oil.

General data: C13H21 NO3, FG = 239.31 g / mol

(4S, 2'S) -4-isopropyl-3- (2-methyl-hept-6-enoyl) -oxazolidin-2-one 22. analogous to Darst. 25 and

(4S, 2'S) -4-isopropyl-3- (2,6-dlmethylhept-6- € noyl) -oxazolidln-2-one 22a.

THERE. Evans, A.E. Weber J. Am. Chem. Soc. 1986, 108, 6757-6761 9.02 ml (9.02 mmol, 1.15 equiv) of a 1 M solution of NaHMDS in THF are cooled to -78 ° C. and dropwise with a solution of 1.88 g (7.84 mmol) of oxazolidinone cooled to 0 ° C. 21 added in 8 ml of THF. The mixture is stirred at -78 ° C. for 1 h, 5.57 g (39.22 mmol, 5 equiv) of Mel dissolved in 2 ml of THF are added and the mixture is stirred at -78 ° C. for 4 h. Then with sat. Quenched NH4CI solution with diethyl ether

ERSATZBI_ATT (RULE 26) extracted, dried over MgS04 and concentrated. The residue is purified by column chromatography with PE: DE = 4: 1. 1.51 g (5.96 mmol, 76%) of the methylated compound are obtained.

General data: C14H23NO3, FG = 253.34 g / mol

Connection 22a is established analogously. From 2.03 g (8.0 mmol) 21a, 1.56 g (5.84 mmol, 73%) are obtained.

(S) -2-methyl-hept-6-en-1-ol 23 and (S) -2,6-dimethylhept-6-en-1-ol 23a

THERE. Evans, A.E. Weber J. Am. Chem. Soc. 1986, 108, 6757-6761

To a solution of 738 mg (2.91 mmol) of the methylated, cooled to 0 ° C.

Compound 22 in 10 ml of diethyl ether is slowly added to 5.83 ml (5.83 mmol, 2 eq.) Of a 1 M suspension of LAH in diethyl ether. It is quenched by adding 221 ml of water, 221 ml of 15% aqueous NaOH solution and 663 ml of water. It is then flash-filtered through Celite with diethyl ether and purified by column chromatography with pentane: DE = 3: 1. 299 mg (2.33 mmol, 80%) of alcohol 23 are obtained as a colorless liquid.

General data: C-8H16O, FG = 128.21 g / mol

Connection 23a is established analogously. From 748 mg (2.80 mmol) 22a. you get

331 mg (2.32 mmol, 83%) 23a.

(S) -2-methyl-hept-6-enal 3. and (S) -2,6-dimethylhept-6-enal 3a

A solution of 295 mg alcohol 23 (2.30 mmol) in 5 ml CH2CI2 is mixed with 1.269 g (2.99 mmol, 1.3 eq.) Dess-Martin periodinane (1,1,1-triacetoxy-1,1,1-dihydro-1,2 - Benziodoxol-3 (1 / - /) - one) added and stirred at RT for 25 minutes. For working up, a volume equivalent of phosphate buffer pH 7 is added. The aqueous phase is extracted with CHoCto, the combined organic phases over MgSC »4 dried and the solvent distilled off on a rotary evaporator. The residue is purified by column chromatography with pentane: DE = 10: 1. 224 mg (1.77 mmol, 77%) of the aldehyde are obtained as a colorless liquid. General data: C8H14O, FG = 126.20 g / mol

Connection 3a is established analogously. 199 mg (1.42 mmol, 71%) 3a are obtained from 284 mg (2.00 mmol) 23a.

Making 4:

ERSATZBI_ATT (RULE 26) Synthesis of segment 4: 3 - [(f-butyidimethylsilyl) oxy] propanal

Synthesis by monosilylation of 1, 3-propanediol and subsequent Swern oxidation of the resulting 3 - [(f-butyldimethylsilyl) oxy] -1-propanol.

General data: CgH2θ> 2 ^Si ; FG = 188.36; CAS number [89922-82-7]

¹³ C-NMR (100 MHz, CDCI ₃ ): d = 202.05 (d), 57.42 (t), 46.58 (t), 25.82 (q), 18.23 (s),

-5.43 (q)

1 - [(f-Butyldimethyisilyl) oxy] -3-hydroxy-4-methyl-4-pentene 10

To 443 mg Mg turnings (18.2 mmol) and 1.5 ml abs. THF under N2 are given 0.2 ml of 2-bromine propene so that the reaction starts. With occasional cooling, a solution of 1.7 ml of 2-bromopropene (22 mmol in total) in 6 ml of abs. THF slowly added dropwise until all the Mg chips have settled. A solution of 2,862 g 1 (15.2 mmol) in 6 ml abs. THF dropped. The mixture is stirred at RT for 6 h. Then 25 ml of sat. NH4CI solution to the reaction solution and allowed to stir for 10 minutes. The mixture is sat in 30 ml. NH4CI solution poured and z. sometimes extracted with ether. The united org. Phases are recorded once with sat. NH4CI solution and sat. NaCI solution washed. It is dried over MgS04, concentrated in vacuo and purified by flash chromatography (EtheπPentan = 1: 6). 2,749 g 2 (11.9 mmol; 79% of theory) are obtained as a colorless oil.

General data: Ci2H26 ° 2 ^Sj : FG = 230.43

¹³ C-NMR (100 MHz, CDCI3): d = 147.10 (s), 110.39 (t), 75.21 (d), 62.17 (t), 36.79 (t),

25.89 (q), 18.41 (s), -5.49 (q), -5.53 (q)

(S) -1, 3-Di - [(tert-Butyldiethylsilyloxy)] - 4-methyl-4-pentene H

11

To a solution of 1, 173 g (4.83 mmol) of (S) -1 - [(fert-butyldimethylsilyloxy)] - 4-methyl-4-penten-3-ol 10 and 855 mg (12.56 mmol, 2.6 eq) imidazole in 15.0 ml of absolute DMF are added to 946 mg (6.28 mmol, 1.3 eq) te / t-butyldimethylchlorosilane. The mixture is stirred at room temperature for 16 h. It is mixed with 50 ml of an aqueous 1M KHS04 solution and extracted four times with 50 ml Et2θ. The combined ether extracts are dried over MgSO4. After the solvent has been distilled off in vacuo, the residue is flash-chromatographed on a silica gel column using pentane / Et2θ (20: 1). As an alternative to this aqueous workup, the reaction mixture can be chromatographed directly. After both work-up variants, 1.643 g (4.73 mmol, 98%) of T are obtained

(S) -3,5-Di - [(tert-Butyidimethylsilyloxy)] - pentan-2-one 12

12th

Ozone in 02 is passed at -78 ° C through a solution of 1, 610 g (4.67 mmol) H in 200 ml absolute dichloromethane (dry ice / acetone cooling bath). If starting compound H can no longer be detected by thin layer chromatography, 3.89 g (14.83 mmol) of triphenylphosphine are added and the cooling bath is removed. The reaction mixture is allowed to slowly come to room temperature and the solvent is distilled off in vacuo. Flash chromatography of the residue through a silica gel column with pentane / Et2θ (50: 1) gives 1.135 g (3.27 mmol, 70%) 12.

ERSATZB.LATT (RULE 26) Diethyl (2-methylthiazol-4-yl) methane phosphonate

P (OEt) ₂

The preparation takes place starting from the literature-known 4-chloromethyl-2-methylthiazole analogous to the instructions for 4-bromomethyl-2-methylthiazole. 7.381 g (50 mmol) of 4-chloromethyl-2-methylthiazole gives 9.971 g (40 mmol, 80%) of diethyl (2-methylthiazol-4-yl) methanephosphonate.

(S, 4 ^ -4- [3,5-Di- (tert-Butyldimethylsilyloxy) -2-methylpent-1-enyi] -2-methylthiazole 13

To a solution of 1, 170 g (4.70 mmol) of diethyl (2-methylthiazol-4-yl) methane phosphonate in 15 ml of absolute THF, 2.94 ml of n-BuLi (1.6 m solution in Hexane). The mixture is stirred at -78 ° C. for 45 min and then a solution of 1.135 g (3.27 mmol) 12 in 10 ml of absolute THF is slowly added dropwise, the mixture is allowed to warm to room temperature and is stirred for a further 12 h at room temperature. The reaction mixture is mixed with 100 ml of saturated NH4CI solution and extracted four times with 80 ml of Et2θ. The combined ether extracts are washed with saturated NaCl solution and dried over MgSO4. After the solvent has been distilled off in vacuo, the residue is flash-chromatographed through a silica gel column using pentane / dichloromethane (2: 3). 1,090 g (2.47 mmol, 75%) 13 are obtained. (S, 4i =) - 3- (fert-Butyldimet ylsilyloxy) -4-met yl-5- (2-methylthiazol-4-yl) -pent-4 → ϊn-1-ol 4

A solution of 442 mg (1.0 mmol) 13 in 40 ml acetonitrile is added dropwise at -20 ° C with 0.45 ml hydrofluoric acid (40%). After adding a few glass fragments or 0.045 ml hexafluorosilicic acid (30%), the mixture is stirred at 0 ° C. until starting compound 13 can no longer be detected in the solution by thin layer chromatography. The reaction mixture is mixed with 50 ml of saturated NaHCO 3 solution and extracted four times with 80 ml of Et 2 O. The combined ether extracts are dried over MgSO4. After the solvent has been distilled off in vacuo, the residue is flash chromatographed on a Kieseigel column with Et2θ. 284 mg (0.87 mmol, 87%) 14 are obtained.

(S, 4i≡) -3- (fert-Butyldimethylsilyioxy) -4-methyl-5- (2-methylthiazol-4-yl) -pent-4-enal 1_5

A suspension of 478 mg (1,127 mmol, 1.3 eq) Dess-Martin periodinane (1, 1, 1 - triacetoxy-1, 1 -dihydro-1, 2-benziodoxol-3 (1 / - /) - on) in 5 , 6 ml of absolute CH CI2 is mixed with a solution of 284 mg (0.87 mmol) 14 in 5.0 ml of absolute CH2CI2 and stirred for 60 min at room temperature. After the solvent has been distilled off in vacuo, the residue is flash chromatographed through a Kieseigel column with pentane / Et2θ (4: 1). 222 mg (0.68 mmol, 78%) 15 are obtained

ERSATZB.LATT (RULE 26) (S, 4 ^ -4- [3- (fert-Butyldimethylsiiyloxy) -2-methyl-hexa-1,5-dienyl] -2-methyl-thiazole 16

440 mg (1.06 mmol, 1.85 eq) of a mixture of equimolar amounts of sodium amide and methyltriphenylphosphonium bromide are stirred for 30 min at room temperature in 4.0 ml of absolute THF. A solution of 185 mg (0.57 mmol) of 15 n 5.0 ml of absolute THF is added, the mixture is stirred for a further 20 min, mixed with 20 ml of saturated NaHCO 3 solution and extracted four times with 30 ml of Et 2 O each. The combined ether extracts are dried over MgSO4. After the solvent has been distilled off in vacuo, the residue is flash-chromatographed on a silica gel column using pentane / Et2θ (20: 1). 151 mg (0.47 mmol, 83%) 16 are obtained.

2-methyl-1- (2-methylthiazol-4-yl) hexa-1,5-dien-3-ol 4

1.18 ml (1.18 mmol, 2.5 eq) of a 1 TBAF solution in THF are stirred in 10 ml of absolute THF for 20 min with activated molecular sieve 4Ä at room temperature in order to bind residual water of the TBAF solution. A solution of 151 mg (0.47 mmol) 16 is added dropwise to the resulting anhydrous TBAF solution at -78 ° C. The mixture is allowed to warm up slowly to room temperature with stirring and hydrolyzed with 50 ml of saturated NH4d solution if starting compound 16 can no longer be detected in the solution by thin layer chromatography. It is extracted three times with 50 ml Et2θ each. After drying over MgSO4, the solvent is removed. Flash chromatographic purification with pentane / Et2θ (20: 1) gives 97 mg (0.465 mmol, 99%) 4.

REPLACEMENT BL. ATT (RULE 26) The representations of compounds of general formula 4a

IF

(B stands for benzyl, p-methoxybenzyl, tetrahydropyranyl or a silyl protective group; e.g. trialkyl or diaryl alkyl silyl protective groups, in particular tert.-butyl-dimethyl, trimethylsilyl and diphenyl-tert.-butyl- silyl groups)

OH by using conventional protective group technique of etherification, see also (D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477).

Preparation of 5 and compounds of the general formula 9a (4 ^, S _! 4R, 5S, 6S) -2- (2,2-dimethyl- [1,3] dioxan-4-yl) -5-hydroxy-2,4, 6-trimethyl-undec-10-en-3-one 5 and

(4 ^, S, 4R, 5S, 6S) -2- (2,2-dimethyl- [1,3] dioxan-4-yl) -5-hydroxy-2,4,6,10-tetramethyl-undec-10 -en-3-one 5a analogous to Scheme 2.

C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn, J. Lampe J. Org. Chem. 1980, 45, 1066

943 microliters (1,509 mmol, 0.98 eq.) Of a 1.6 M solution of n-BuLi in hexane are added to a solution of 153 mg (1.509 mmol, 0.98 eq.) In 1.5 ml THF at 0 ° C added dropwise and stirred for 30 minutes before cooling to -78 ° C. 330 mg (1,540 mmol, 1 eq.) (S) -2- (2,2-dimethyl- [1, 3] dioxan-4-yl) -2-methylpentan-3-one Z _<are dissolved in 1 ml of THF slowly added dropwise. The solution is stirred at -78 ° C for 1 h. 194 mg (1,540 mmol, 1 eq.) (S) -2-methyl-hept-6-enal 3 are then added dropwise and the mixture is stirred at -78 ° C. for 45 minutes. The reaction solution is quenched by adding saturated NH4Cl solution and warmed to RT. The aqueous phase is extracted with ether, the combined organic phases are dried over MgSO 4 and the solvent is distilled off on a rotary evaporator. The residue is purified by column chromatography with pentane: diethyl ether = 3: 1. 369 mg (1,084 mmol, 70%) of aldol product 5 are obtained as a colorless oil. General data: C20H36O4, FG = 340.50 g / mol

Connection 5a is made analogously. From 238 mg (1.70 mmol) 3a, 386 mg (1.09 mmol, 64%) 5a are obtained.

(3S, 6R, 7S, 8S) -1, 3,7-trihydroxy-4,4,6,8-tetramethyl-tridec-12-en-5-one 6 and (3S, 6R, 7S, 8S) -1 , 3,7-trihydroxy-4,4,6,8,12-pentamethyl-tridec-12-en-5-one

6a

L A. Paquette, DR Sauer, DG Cleary, MA Kinsella, CM Blackwell, L G. Anderson J. Am. Chem. Soc. 1992, 114, 7375-7387. A solution of 100 mg (0.294 mmol) of the aldol product 5_ in 14 ml MeOH is mixed with 95 mg (0.378 mmol, 1.3 eq.) PPTS, stirred for 36 h at RT and then quenched by the addition of 33 drops of saturated NaHCO 3 solution. The mixture is concentrated on a rotary evaporator and the residue is taken up in ether. It is washed with saturated NaCl solution and the aqueous phase is extracted with ether. The combined organic phases are dried over MgSO4 and the solvent is distilled off on a rotary evaporator. The residue is purified by column chromatography with diethyl ether. 78 mg (0.260 mmol, 88%) of the triol 6 are obtained as a colorless oil. General data: C17H32O4, FG = 300.44 g / mol

Connection 6a is established analogously. 96 mg (0.270 mmol) 5a gives 77 mg (0.246 mmol, 91%) §a.

(3S, 6R, 7S, 8S) -1,3,7-tri- (tert-butyldimethylsllyloxy) -4,4,6,8-tetramethyl-tridec-12-en-5-one 7 and (3S, 6R , 7S, 8S) -1,3,7-tri- (tert-butyldimethylsilyloxy) -

4,4,6,8,12-pentamethyl-tridec-12-en-5-one Za

Yuanwei Chen, Pierre Vogel, J. Org. Chem. 1994, 59, 2487-2496

To a solution of 225 mg (0.749mmol) of the triol 6 in 13 ml, cooled to -78 ° C

CH2CI2 963 mg (8.99 mmol, 12 eq.) 2,6-lutidine and 1188 mg (4.49 mmol, 6 eq.) Te / τ-butyldimethylsilyltrifluoromethanesulfonate are slowly added dropwise. One leaves 30

Stir for minutes at -78 ° C and 3 h at 0 ° C and quench with saturated NaHC03-

Solution. The aqueous phase is extracted with CH2Cl2. The united organic

Phases are dried over MgS04 and the solvent on

Distilled off rotary evaporator. The residue is column chromatographed with

Pentane: diethyl ether = 30: 1 purified. 462 mg (0.719 mmol, 96%) of the trisilylated product 7 are obtained as a colorless oil.

General data: C35H74θ4Si3, FG = 643.22 g / mol

Connection 7a is established analogously. From 204 mg (0.650 mmol) 6a 423 mg (0.644 mmol, 99%) are obtained.

(3S, 6R, 7S, 8S) -3,7-di- (fert-butyldimethylsilyloxy) -1-hydroxy-4,4,6,8-tetra-methyl-tridec-12-en-5-one fl and ( 3S, 6R, 7S, 8S) -3,7-di- (fert-butyldimethylsilyloxy) -1-hydroxy -4,4,6, 8,12-penta-methyl-tridec-12-en-5-one §A

K.C. Nicolaou, K.R. Reddy, G. Skokotas, F. Sato, X.-Y. Xiao J. Am. Chem. Soc. 1992, 114, 7935. A solution of 156 mg (0.243 mmol) of the trisilylated compound 7_ in 6.5 ml MeOH and 6.5 ml CH2Cl2 is cooled to 0 ° C. and 11 mg camphorsulfonic acid (0.0485 mmol, 0.2 eq.) Are added. After stirring at 0 ° C. for 5 h, the mixture is quenched by adding saturated NaHCO 3 solution. The aqueous phase is extracted with CH2Cl2. The combined organic phases are dried over MgSO4 and the solvent is distilled on a rotary evaporator. The residue is purified by column chromatography with pentane: diethyl ether = 3: 1. 105 mg (0.199 mmol, 82%) of alcohol 8 are obtained as a colorless oil.

General data: C29H6θθ4Si2, FG = 528.96 g / mol

Connection 8a is established analogously. From 152 mg (0.232 mmol) 7a, 101 mg (0.186 mmol, 80%) 8a are obtained.

(3S, 6R, 7S, 8S) -3,7-DI- (fert-butyldimethylsilyloxy) -4,4,6,8-tetraethyl-5-oxotridec-12-enoic acid 9 and (3S, 6R, 7S, 8S) -3,7-DI- (fert-butyldimethylsilyloxy) - 4,4,6,8, 12-pβntamethyl-5-oxo-trldec-12-enoic acid 9a.

E. J. Corey, G. Schmidt, Tetrahedron Lett. 1979, 399-402 2371 mg (6.30 mmol, 11 eq.) Of PDC dissolved in 3 ml of DMF are added dropwise to a solution of 303 mg (0.573 mmol) of alcohol 8. in 6 ml of DMF at 0 ° C. The mixture is stirred at RT for 36 h and then poured into 50 ml of saturated NaCl solution, diluted with water and extracted with CH2Cl2. The combined organic phases are dried over MgSO4 and the solvent is distilled off on a rotary evaporator. The

REPLACEMENT BI ATT (RULE 26) The residue is purified by column chromatography using pentane: diethyl ether = 2: 1. 247 mg (0.455 mmol, 79%) of acid 9 are obtained as a colorless oil. General data: C29H58θsSi2, FG = 542.94 g / mol, compound 2a is prepared analogously. From 320 mg (0.590 mmol) §a one obtains 273 mg (0.490 mmol, 83%) Sa

(3S, 6R, 7S, 8S) -3,7-di-fert-butyldimethylsilyloxy-4,4,6,8-tetramethyl-5-oxo-tridθc-12-enoic acid- (1 S) -1 - [(£ ) -1-methyl-2- (2-methylthlazol-4-yl) vinyl] but-3-enyl ester 17 and

* (3S, 6 7,7S, 8 ^ -3,7-DI-ter-butyldlmet ylsilyloxy-4,4,6,8,12-penta-methyl-5-oxotridec-12-enoic acid- (1 S. ) -1 - [(£) -1 -methyl-2- (2-methylthia. Zol-4-yl) vinyl] but-3-enyl ester 17a

Esterification according to B. Neises, W. Steglich Angew. Chem. 1978, 90, 556. A solution of 145 mg (0.268 mmol) acid 9, 56 mg (0.268 mmol) alcohol 4 and 6.5 mg (0.0536 mmol, 0.2 eq) DMAP in 1.5 ml absolute CH2CI2 is added 0 ° C with 72 mg (0.348 mmol, 1.3 eq) dicyclohexylcarbodiimide. The mixture is stirred at 0 ° C. for 10 min and at room temperature for 12 h. After removal of the solvent and flash chromatography of the residue with pentane / Et2θ (20: 1), 157 mg (0.214 mmol, 80%) of the ester 17 are obtained.

* Ester 17a is represented analogously. 166 mg (0.222 mmol, 74%) 17a are obtained from 167 mg (0.30 mmol) 9a and the equimolar amount 4.

ERSATZB.LATT (RULE 26) (4S, 7H, 8S, 9S, 16S, 13Z) -4,8-di-fert-butyldimΘthylsilyloxy-5 _τ 5,7,9-tΘtra-methyl-16- [(£) -1-methyl-2- ( 2-methylthiazol-4-yl) vinyl] -1-oxa-cyclohexadec-13-ene-2,6-dione 18 and

* (4S, 7ff, 8S, 9S, 16S, 13Z) -4,8-di-fert-butyldimethylthylsilyloxy-5,5,7,9,13-pentamethyl-16 - [(£) -1-methylth- 2- (2-methylthiazol-4-yl) vinyl] -1-oxa-cyclohexadec-13-en-2,6-dione

An Ar-saturated solution of 49.3 mg (0.0671 mmol) of the ester \ _ in 33.5 ml of absolute CH2CI2 (corresponding to a substrate concentration of 0.002 M) is mixed with 3.3 mg (6 mol%) Cl2 [Ru = CHPh] (PCy3) 2 (Cy = cyclohexyl) stirred under an argon atmosphere for 16 h. After removal of the solvent and flash chromatography of the residue with pentane / Et2θ (20: 1), 44 mg (0.0630 mmol, 94%) of compound 18 are obtained as a 1: 1 mixture with its E-isomer. * 49.0 mg (0.068 mmol, 68%) of a mixture of 18a and its E isomer are obtained analogously from 74.8 mg (0.100 mmoh 17a).

(4S, 7 7,8S, 9S, 16S, 1 ^ -4,8-Dlhydroxy-5,5,7,9-tetra-methyl-16 - [(£) -1-methyl-2- (2-methyl -thiazol-4-yl) -vinvπ-1-oxa-cvclohexadec-13-en-2.6-dione 19 ("Epothilon C") and

* (4S, 7 /?, 8S, 9S, 16S, 132) -4,8-DIhydroxy-5,5,7,9,13-penta-methyl-16 - [(£) -1-methyl-2- (2-methylthiazol-4-yl) vinyl] -1-oxa-cyclohexadec-13-en-2,6-dione 19a ("epothilone D")

A solution of 35.3 mg (0.05 mmol) 18 (ZE mixture 1: 1) in 2.4 ml acetonitrile / Et2θ (1: 1) is added dropwise at 0 ° C with 0.27 ml hydrofluoric acid (40%) . After adding a few pieces of glass or 0.027 ml Hexafluorosilicic acid (30%) is stirred for 17 h at room temperature. The reaction mixture is mixed with 10 ml of saturated NaHCO 3 solution and extracted three times with 20 ml of Et 2 O. The combined ether extracts are dried over MgSO4. After distilling off the solvent in vacuo, the residue is flash chromatographed on a silica gel column using Et2θ. 16.5 mg (0.0325 mmol, 65%) of l £ are obtained as a 1: 1 Z: E mixture.

* 20.7 mg (0.042 mmol, 70%) J ta (as Z: E mixture) are obtained analogously from 43.2 mg (0.06 mmol) 18a.

Epothilon A 1 and * Epothilon B la

1a R = Me

A solution of 14.3 mg (0.03 mmol) 19 (1: 1-Z: E mixture. In 2.5 ml CH2Cl2 is added to

-35 ° C while stirring dropwise with 0.36 ml (0.035 mmol, 1.2 eq) of a freshly prepared solution of dimethyldioxirane in acetone. The mixture is stirred at -35 ° C. for 2 h, then 5 ml of a 10% strength aqueous solution of iron (II) sulfate are added and the mixture is extracted three times with 10 ml of CH 2 Cl 2 each. After the solvent has been distilled off in vacuo, the residue is flash chromatographed on a silica gel column using Et2θ. 7.1 mg (0.0144 mmol, 48%) of epothilone A are obtained. * 6.2 mg (0.0123 mmol, 41%) of epothilone B are obtained analogously from 14.8 mg (0.03 mmol) of 19a.

The invention also relates to stereoisomers of the compounds according to the claims, as are usually obtained during synthesis.

Claims

claims

1.) Process for the preparation of epitholone A or B of the general formula 1

wherein R = hydrogen (A) or a methyl group (B), characterized in that a thiazolalkyldiene alcohol derivative of the formula 4

OH

with a carboxylic acid of the general formula 9a

where B = benzyl, tetrahydropyranyl and / or a silyl protective group (s) and R = hydrogen or methyl,

CORRECTED SHEET (RULE 91) ISA / EP is esterified, the ester obtained is ring-closed by means of an oxygen metathesis in the presence of a noble metal catalyst, the hydroxyl protective groups are optionally cleaved, the newly formed double bond is epoxidized and the hydroxyl protective groups are optionally cleaved.

2.) Deoxy-epothilones according to general formula 19a

where B = hydrogen, benzyl, p-methoxybenzyl, tetrahydropyranyl and / or a silyl protective group (s) and R = hydrogen or methyl,

3.) 2- (2,2-dimethyl- [1,3] dioxan-4-yl) -2-methylpentan-3-one 2

4.) 2-Methy! -6-heptenal 3

H

CORRECTED SHEET (RULE 91) ISA / EP

5.) 2,6-Dimethyl-6-heptenal 3a

6.) Compounds of the general formula 9a

where B = benzyl, tetrahydropyranyl and / or a silyl protecting group (s) and R = hydrogen or methyl, and the meaning of B in the molecule can be different.

7.) Compounds of the general formula 4a

4a

OB in what

B = hydrogen, benzyl, p-methoxybenzyl, tetrahydropyranyl or a silyl protecting group.

8.) (4S, 6S) -2- (2,2-dimethyl- [1,3] dioxan-4-yl) -5-hydroxy-2,4,6-thmethyl-undecan-3-one _5

9.) Stereoisomers of the compounds according to claims 1-6.

CORRECTED SHEET (RULE 91)