DE19636343C1 - New (di:methyl)-dioxanyl-methyl-pentanone and related compounds - Google Patents

New (di:methyl)-dioxanyl-methyl-pentanone and related compounds

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DE19636343C1
DE19636343C1 DE19636343A DE19636343A DE19636343C1 DE 19636343 C1 DE19636343 C1 DE 19636343C1 DE 19636343 A DE19636343 A DE 19636343A DE 19636343 A DE19636343 A DE 19636343A DE 19636343 C1 DE19636343 C1 DE 19636343C1
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mmol
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tert
mixture
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Dieter Schinzer
Anja Limberg
Oliver M Boehm
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Novartis AG
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Schering AG
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Priority to DE19645361A priority patent/DE19645361A1/en
Priority to EP97914077A priority patent/EP0923583A1/en
Priority to AU21493/97A priority patent/AU716610B2/en
Priority to NZ334821A priority patent/NZ334821A/en
Priority to JP10511141A priority patent/JP2001500851A/en
Priority to PCT/DE1997/000111 priority patent/WO1998008849A1/en
Priority to US08/921,512 priority patent/US5969145A/en
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Priority to US09/344,713 priority patent/US6043372A/en
Priority to US09/478,466 priority patent/US6156905A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

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Abstract

The compounds below and their stereoisomers are new. a) 2-(2,2-dimethyl-1,3-dioxan-4-yl)-2-methyl-pentan-3-one (3); b) 6-(tert.-butyldimethylsilyl)oxy-2-methyl-hexanal (4); c) (S,4E)-3-benzyloxy-1-(tert.-butyldimethylsilyl)oxy-4-methyl-5-(2-ethyl thiazol-4-yl)-pent-4-ene (8); d) (4S,6S)-10-(tert.-butyldimethylsilyloxy)-2-(2,2-dimethyl-1,3-dioxan-4- yl)-5-hydroxy-2,4,6-trimethyl-decan-3-one (80); and e) (3S,6R,7S,8S)-7-benzyloxy-3-(tert.-butyldimethylsilyloxy)-12-(tert.but yldiphenylsilyloxy)-4,4,6,8-tetramethyl-5-oxo-dodecanoic acid (87).

Description

Die Erfindung betrifft Zwischenprodukte innerhalb der Totalsynthese von Epothilon A und B. Epothilon A und B sind Naturstoffe, die durch Mikroorganismen hergestellt werden können und die Taxol ähnliche Eigenschaften besitzen und somit besonderes Interesse in der Arzneimittelchemie besitzen. Diese Epothilone A und B werden innerhalb des Standes der Technik in DE 41 38 042 C2 und in European Chemistry Chronicle, Vol. 1/ No. 1 S. 7-10 beschrieben.The invention relates to intermediates within the total synthesis of epothilone A and B. Epothilones A and B are natural products produced by microorganisms and the Taxol have similar properties and thus have special interest in drug chemistry. These epothilones A and B are within the state of the art in DE 41 38 042 C2 and in European Chemistry Chronicle, Vol. 1 / No. 1 pp. 7-10.

Aufgabe der vorliegenden Erfindung ist es, Zwischenprodukte für die Totalsynthese von Epothilon A und B bereitzustellen, die es erlauben, die Naturstoffe einfach herzustellen und ebenso die Strukturen in der üblichen Art und Weise zu variieren, um Verbindungen mit stärkeren bzw. nebenwirkungsärmeren Eigenschaften herstellen zu können.The object of the present invention is to provide intermediates for total synthesis of epothilones A and B, which allow the natural products to be easily to manufacture and also to vary the structures in the usual way, to compounds with stronger or less side effects to be able to manufacture.

Zunächst erfolgt die Beschreibung der Synthesestrategie, danach die detaillierte Synthese der Schlüsselsegmente, 2-(2,2-Dimethyl-[1,3]dioxan-4-yl)-2-methyl­ pentan-3-on 3, 6-[(tert.-Butyldimethylsilyl)oxy]-2-methyl-hexanal 4, dem Thiazol­ derivat 8 und (4S,6S)-10-(tert.Butyldimethylsilyloxy)-2-(2,2-dimethyl-[1,3]-dioxan-- 4-yl)-5-hydroxy-2,4,6,-trimethyl-decan-3-on (dem Aldolreaktionsprodukt aus 3 und 4 und (3S,6R,7S,8S)-7-Benyloxy-3-(tert.-butyldimethylsilyloxy)-12-(tert.-b-utyldiphenyl­ silyloxy)-4,4,6,8-tetramethyl-5-oxo-dodecansäure 87. Diese Synthone werden zwangsläufig benötigt, um die Naturstoffe stereospezifisch erstellen zu können. Das folgende Schema zeigt den retrosynthetischen Weg, auf welchem Wege die Natur­ stoffe synthetisiert werden (nachveröffentlicht in Chem. Eur. J. 1996, 2,1477).First the synthesis strategy is described, then the detailed one Synthesis of the key segments, 2- (2,2-dimethyl- [1,3] dioxan-4-yl) -2-methyl pentan-3-one 3,6 - [(tert-butyldimethylsilyl) oxy] -2-methyl-hexanal 4, the thiazole derivative 8 and (4S, 6S) -10- (tert-butyldimethylsilyloxy) -2- (2,2-dimethyl- [1,3] -dioxane-- 4-yl) -5-hydroxy-2,4,6, -trimethyl-decan-3-one (the aldol reaction product from 3 and 4 and (3S, 6R, 7S, 8S) -7-benyloxy-3- (tert-butyldimethylsilyloxy) -12- (tert-b-utyldiphenyl silyloxy) -4,4,6,8-tetramethyl-5-oxododecanoic acid 87. These synthons are inevitably required to create the natural products stereospecifically. The The following diagram shows the retrosynthetic way, in which way nature substances are synthesized (republished in Chem. Eur. J. 1996, 2,1477).

Schema 1 Scheme 1

Retrosynthetische Analyse Retrosynthetic analysis

Schema 2 Scheme 2

Synthese von Segment 3 Synthesis of segment 3

Arbeitsvorschriften zur Synthese von Segment 3Working instructions for the synthesis of segment 3 (2-(2,2-Dimethyl-[1,3]dioxan-4-yl)-2-methyl-pentan-3-on)(2- (2,2-dimethyl- [1,3] dioxan-4-yl) -2-methylpentan-3-one)

Das 3-[(tert-Butyldimethylsilyl)oxy]propanal 5 wird ausgehend von Propan-1,3-diol 13 hergestellt, indem zunächst nach einer Methode von P.G. McDougal, J.G. Rico, Y. Oh, B.D. Condon, J. Org. Chem. 1986, 51, 3388-3390, zum 3-[(tert- Butyldimethylsilyl)oxy]-1-propanol 14 monosilyliert wird, das anschließend mit DMSO/Oxalylchlorid zum Aldehyd 5 oxidiert wird (A. Jenmalm, W. Berts, Y. Li, K. Luthmann, I. Csregh, U. Hacksell, J. Org. Chem. 1994, 59, 1139-1148). The 3 - [(tert-butyldimethylsilyl) oxy] propanal 5 is based on propane-1,3-diol 13 by first using a method of P.G. McDougal, J.G. Rico, Y. Oh, B.D. Condon, J. Org. Chem. 1986, 51, 3388-3390, zum 3 - [(tert- Butyldimethylsilyl) oxy] -1-propanol 14 is monosilylated, which then with DMSO / oxalyl chloride is oxidized to aldehyde 5 (A. Jenmalm, W. Berts, Y. Li, K. Luthmann, I. Csregh, U. Hacksell, J. Org. Chem. 1994, 59, 1139-1148).  

Darstellung von 1-[(tert-Butyldimethylsilyl)oxy]-4,4-dimethyl-hex-5-en-3-ol 15Preparation of 1 - [(tert-butyldimethylsilyl) oxy] -4,4-dimethyl-hex-5-en-3-ol 15

(H.C. Brown, P.K Jadhav, Tetrahedron Lett. 1984, 25, 1215-1218; P.K Jadhav, K.S. Bhat und P. Thirumalai, H.C. Brown, J. Org. Chem. 1986, 51, 432-439).
Zu einer auf -25°C gekühlten Suspension von Isopinocamphenylboran (Ipc₂BH) (7.34 mmol, hergestellt aus (-)--Pinen [99%, 97% optische Aktivität (ee)] H.C. Brown, M.C. Desai, P.K Jadhav, J. Org. Chem. 1982, 47, 5065-5069; H.C. Brown, B. Singaram, J. Org. Chem. 1984, 49, 945-947) in 2.6 ml THF wird 500 mg (7.34 mmol, 1 equiv) 3-Methyl-1,2-butadien langsam zugetropft und die Reaktionsmischung 6 h bei -25°C gerührt. Das THF wird anschließend abgepumpt bei RT (14 bar/1 h), (0.5 mm/2 h) und der Rückstand in 10.5 ml Diethylether gelöst. Die Lösung wird auf -78°C gekühlt und 1.382 g (7.34 mmol, 1 equiv) Aldehyd 5 zugetropft. Man löst 12 h bei -78°C rühren und läßt dann auf RT erwärmen. Die Reaktionsmischung wird mit 10.7 ml 3 N NaOH-Lösung versetzt, danach mit 4.4 ml 30%iger H₂O₂-Lösung und 2 h unter Rückfluß erhitzt. Die organische Phase wird abgetrennt, mit 15 ml H₂O und 15 ml ges. NaCl-Lösung gewaschen, über MgSO₄ getrocknet und eingeengt. Der Rückstand wird säulenchromatographisch mit Pentan : Diethylether = 2 : 1 gereinigt und man erhält 800 mg (3.098 mmol) des Alkohols 15, entsprechend einer Ausbeute von 42%. Die Bestimmung des Enantiomerenüberschusses erfolgte durch GC-analytische Untersuchung der diastereomeren Verbindungen, die bei der Veresterung des Alkohols mit (1R)-(-)-Camphansäurechlorid erhalten werden und ergab eine optische Aktivität (ee) von 92%.
Allgemeine Daten: C₁₄H₃₀O₂Si, FG = 258.47 g/mol
¹³C-NMR (100 MHz, CDCl₃): 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).(HC Brown, PK Jadhav, Tetrahedron Lett. 1984, 25, 1215-1218; PK Jadhav, KS Bhat and P. Thirumalai, HC Brown, J. Org. Chem. 1986, 51, 432-439).
To a suspension of isopinocamphenylborane (Ipc₂BH) (7.34 mmol, made from (-) - pinene [99%, 97% optical activity (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 was slowly added dropwise and the reaction mixture was stirred at -25 ° C. for 6 h. The THF is then pumped off at RT (14 bar / 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 5 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 3 N 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: diethyl ether = 2: 1 and 800 mg (3,098 mmol) of the alcohol 15 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 (1R) - (-) - camphanoyl chloride and gave an optical activity (ee) of 92%.
General data: C₁₄H₃₀O₂Si, FG = 258.47 g / mol
13 C-NMR (100 MHz, CDCl₃): 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).

Darstellung von 4-(1,1-Dimethyl-allyl)-2,2-dimethyl-[1,3]dioxan 16Preparation of 4- (1,1-dimethyl-allyl) -2,2-dimethyl- [1,3] dioxane 16

Es werden 278 mg (1.076 mmol) des Alkohols 15 in 13 ml Aceton gelöst und 400 mg (2.51 mmol, 2.3 eqiuv) wasserfreies CuSO₄ zugegeben. Dann werden 20 Tropfen einer Lösung von 0.1 ml Eisessig in 1 ml CH₂Cl₂ zugetropft und 12 h bei RT gerührt. Falls sich DC-chromatographisch noch Edukt nachweisen läßt, wird weitere Säurelösung zugegeben, bis die Umsetzung vollständig ist. Zur Aufarbeitung wird das Reaktionsgemisch auf ges. NaHCO₃-Lösung gegossen und die wäßrige Phase mit DE extrahiert. Die vereinigten organischen Phasen werden über MgSO₄ getrocknet und am Rotationsverdampfer eingeengt. Der Rückstand wird säulenchromatographisch mit Pentan : Diethylether = 2 : 1 gereinigt. Man erhält 161 mg (0.87 mmol) des Acetonids 16 entsprechend einer Ausbeute von 81%.
Allgemeine Daten: C₁₁H₂₀O₂, FG = 184.28 g/mol
¹³C-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).278 mg (1,076 mmol) of alcohol 15 are dissolved in 13 ml of acetone and 400 mg (2.51 mmol, 2.3 eqiuv) of anhydrous CuSO₄ are added. Then 20 drops of a solution of 0.1 ml of glacial acetic acid in 1 ml of 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 NaHCO₃ solution and extracted the aqueous phase with DE. The combined organic phases are dried over MgSO₄ and concentrated on a rotary evaporator. The residue is purified by column chromatography with pentane: diethyl ether = 2: 1. 161 mg (0.87 mmol) of acetonide 16 are obtained, corresponding to a yield of 81%.
General data: C₁₁H₂₀O₂, FG = 184.28 g / mol
13 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).

Darstellung von 2-(2,2-Dimethyl-[1,3]dioxan-4-yl)-2-methyl-propionaldehyd 17Preparation of 2- (2,2-dimethyl- [1,3] dioxan-4-yl) -2-methyl-propionaldehyde 17

Es werden 286 mg (1.55 mmol) des Acetonids 16 in 18 ml THF gelöst und 14 ml wäßriger Phosphatpuffer pH 7 zugegeben. Zu der kräftig gerührten Reaktionsmischung wird 400 µl (0.031 mmol, 0.02 equiv) OsO₄-Lösung (2.5%ig in tert-Butanol) zugetropft. Nach 10 min. werden 996 mg (4.656 mmol, 3 equiv) NalO₄ portionsweise über einen Zeitraum von 20 min. zugegeben. Die Mischung wird kräftig bei RT gerührt und nach 24 und 48 h jeweils weitere 332 mg (je 1.55 mmol, 2 × 1.0 equiv) NalO₄ addiert. Nach 55 h werden die Phasen getrennt, die wäßrige Phase mit Diethylether extrahiert, die vereinigten organischen Phasen über MgSO₄ getrocknet und eingeengt. Der Rückstand wird säulenchromatographisch mit Pentan : Diethylether = 1 : 1 gereinigt. Man erhält 221 mg (1.19 mmol) des Aldehyds 17 entsprechend einer Ausbeute von 76%.
Allgemeine Daten: C₁₀H₁₈O₃, FG = 186.25 g/mol
¹³C-NMR (100 MHz, CDCl₃): 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).286 mg (1.55 mmol) of the acetonide 16 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 tert-butanol) is added dropwise to the vigorously stirred reaction mixture. After 10 min. 996 mg (4,656 mmol, 3 equiv) NalO₄ in portions over a period of 20 min. admitted. The mixture is stirred vigorously at RT and after 24 and 48 h a further 332 mg (1.55 mmol, 2 × 1.0 equiv) of NalOal are added. After 55 h the phases are separated, the aqueous phase is extracted with diethyl ether, the combined organic phases are dried over MgSO₄ and concentrated. The residue is purified by column chromatography with pentane: diethyl ether = 1: 1. 221 mg (1.19 mmol) of aldehyde 17 are obtained, corresponding to a yield of 76%.
General data: C₁₀H₁₈O₃, FG = 186.25 g / mol
13 C-NMR (100 MHz, CDCl₃): 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).

Darstellung von 2-(2,2-Dimethyl-[1,3]dioxan-4-yl)-2-methyl-pentan-3-ol 18Preparation of 2- (2,2-dimethyl- [1,3] dioxan-4-yl) -2-methyl-pentan-3-ol 18

Eine Lösung von 268 mg (1.44 mmol) des Aldehyds 17 in 4 ml Diethylether wird bei 0°C mit 528 µl (1.58 mmol, 1.1 equiv) einer 3 M Lösung von EtMgBr in Diethylether versetzt. Man läßt 2 h bei 0°C rühren, erwärmt auf RT und läßt eine weitere Stunde rühren. Zur Aufarbeitung wird mit ges. wäßriger NH₄Cl-Lösung versetzt und dann soviel Wasser zugegeben bis der Niederschlag in Lösung geht. Die wäßrige Phase wird mit Diethylether extrahiert, die vereinigten organischen Phasen über MgSO₄ getrocknet und eingeengt. Der Rückstand wird säulenchromatographisch mit Pentan : Diethylether = 1 : 1 gereinigt. Man erhält 251 mg (1.16 mmol) des Alkohols 18, entsprechend einer Ausbeute von 80%.
Allgemeine Daten: C₁₂H₂₄O₃, FG = 216.31 g/mol
¹³C-NMR (100 MHz, C₆D₆): 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)
¹³C-NMR (100 MHz, C₆D₆): 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). A solution of 268 mg (1.44 mmol) of the aldehyde 17 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 diethyl 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 NH₄Cl solution was added and then enough water was added until the precipitate dissolved. The aqueous phase is extracted with diethyl ether, the combined organic phases dried over MgSO₄ and concentrated. The residue is purified by column chromatography with pentane: diethyl ether = 1: 1. 251 mg (1.16 mmol) of alcohol 18 are obtained, corresponding to a yield of 80%.
General data: C₁₂H₂₄O₃, FG = 216.31 g / mol
13 C-NMR (100 MHz, C₆D₆): 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, C₆D₆): 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).

Darstellung von 2-(2,2-Dimethyl-[1,3]dioxan-4-yl)-2-methyl-pentan-3-on 3Preparation of 2- (2,2-dimethyl- [1,3] dioxan-4-yl) -2-methyl-pentan-3-one 3

W.P. Griffith, S.V. Ley, G.P. Whitcombe, A.D. White, J. Chem. Soc., Chem. Commun. 1987, 1625-1627.
Es werden 70 mg (0.32 mmol) des Alkohols 18 in 5 ml CH₂Cl₂ gelöst und 64 A Molsiebkugeln und 66 mg (0.48 mmol, 1.5 equiv) 4-Methylmorpholin N-OXID (NMO) zugegeben. Nach 10 min Rühren werden 6 mg Tetrapropylammonium-per­ ruthenat(VII) (TPAP) (0.016 mmol, 0.05 Äquivalente) addiert und 4 Stunden bei RT gerührt. Danach wird die Reaktionsmischung am Rotationsverdampfer eingeengt und direkt säulenchromatographisch mit Pentan : Diethylether = 1 : 1 gereinigt. Man erhält 60 mg (0.28 mmol) des Ethylketons 3, entsprechend einer Ausbeute von 86%.
Allgemeine Daten: C₁₂H₂₂O₃, FG = 214.30 g/mol
¹³C-NMR (100 MHz, C₆D₆): 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). WP Griffith, SV Ley, GP Whitcombe, AD White, J. Chem. Soc., Chem. Commun. 1987, 1625-1627.
70 mg (0.32 mmol) of the alcohol 18 are dissolved in 5 ml of CH₂Cl₂ and 64 A molecular sieve balls and 66 mg (0.48 mmol, 1.5 equiv) 4-methylmorpholine N-OXID (NMO) are added. After stirring for 10 min, 6 mg of tetrapropylammonium per ruthenate (VII) (TPAP) (0.016 mmol, 0.05 equivalents) are added and the mixture is stirred at RT for 4 hours. The reaction mixture is then concentrated on a rotary evaporator and purified directly by column chromatography with pentane: diethyl ether = 1: 1. 60 mg (0.28 mmol) of ethyl ketone 3 are obtained, corresponding to a yield of 86%.
General data: C₁₂H₂₂O₃, FG = 214.30 g / mol
13 C-NMR (100 MHz, C₆D₆): 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).

Schema 3 Scheme 3

Synthese von Segment 4 Synthesis of segment 4

Arbeitsvorschriften zur Darstellung von Segment 4Work regulations for the presentation of segment 4

Das Natrium-6-hydroxyhexanoat 20 wird nach einer Vorschrift von Wulff, Krüger und Röhle Chem. Ber. 1971, 104, 1387-1399 aus ω-Caprolacton 19 hergestellt.The sodium 6-hydroxyhexanoate 20 is produced according to a regulation by Wulff, Krüger and Röhle Chem. Ber. 1971, 104, 1387-1399 made from ω-caprolactone 19.

Darstellung von 6-[(tert-Butyldimethylsilyl)oxy)-hexansäuresilylester 21Preparation of 6 - [(tert-butyldimethylsilyl) oxy) hexanoic acid silyl ester 21

E. J. Corey, A. Venkanteswarlu, J. Am. Chem. Soc. 1972, 94, 6190-6191.
Eine Mischung aus 2.00 g (12.97 mmol) des Salzes 20, 25 ml DMF, 5.87 g (38.93 mol, 3 equiv) TBDMSCI und 5.3 g (77.85 mmol, 6 equiv) Imidazol wird 48 h bei RT gerührt. Das Reaktionsgemisch wird flashfiltriert und anschließend mit Pentan : DE = 4 : 1 säulen-chromatographisch gereinigt. Man erhält 3.99 g (11.1 mmol) der bissilylierten Verbindung 21, entsprechend einer Ausbeute von 85%.
Allgemeine Daten: C₁₈H₄₀O₃Si₂, FG = 360.69 g/mol
¹³C-NMR (100 MHz, CDCl₃): 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).EJ Corey, A. Venkanteswarlu, J. Am. Chem. Soc. 1972, 94, 6190-6191.
A mixture of 2.00 g (12.97 mmol) of the salt 20, 25 ml of DMF, 5.87 g (38.93 mol, 3 equiv) TBDMSCI and 5.3 g (77.85 mmol, 6 equiv) imidazole is stirred at RT for 48 h. 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 21 are obtained, corresponding to a yield of 85%.
General data: C₁₈H₄₀O₃Si₂, FG = 360.69 g / mol
13 C-NMR (100 MHz, CDCl₃): 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).

Darstellung von 6-[(tert-Butyldimethylsilyl)oxy]-hexansäure 22Preparation of 6 - [(tert-butyldimethylsilyl) oxy] hexanoic acid 22

nach D.R. Morton, J.L. Thompson, J. Org. Chem. 1978, 43, 2102-2106.
Eine Lösung von 3.25 g (9.02 mmol) der bissilylierten Verbindung 21 in 130 ml Methanol und 44 ml THF wird mit einer Lösung von 4.4 g (31.8 mmol, 3.5 equiv) K₂CO₃ in 44 ml H₂O versetzt und 1 h bei RT gerührt. Danach wird das Volumen der Reaktionslösung im Vakuum auf ein Viertel reduziert. Man verdünnt mit 130 ml ges. NaCl-Lösung und stellt mit 1 M KHSO₄-Lösung auf pH 4-5 ein. Es wird mit Diethylether extrahiert. Die vereinigten organischen Phasen werden über MgSO₄ getrocknet und das Lösungsmittel am Rotationsverdampfer abdestilliert. Man erhält 2.01 g (8.17 mmol) der Carbonsäure 22, entsprechend einer Ausbeute von 90%.
Allgemeine Daten: C₁₂H₂₆O₃Si, FG = 246.42 g/mol
¹³C-NMR (100 MHz, CDCl₃): 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). 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 21 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) of K₂CO₃ in 44 ml of H₂O and stirred for 1 h at RT. The volume of the reaction solution is then reduced to a quarter in vacuo. It is diluted with 130 ml of sat. NaCl solution and adjust to pH 4-5 with 1 M KHSO₄ 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. 2.01 g (8.17 mmol) of carboxylic acid 22 are obtained, corresponding to a yield of 90%.
General data: C₁₂H₂₆O₃Si, FG = 246.42 g / mol
13 C-NMR (100 MHz, CDCl₃): 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).

Darstellung von 6-[(tert-Butyldimethylsilyl)oxy]-hexanoylchlorid 23Preparation of 6 - [(tert-butyldimethylsilyl) oxy] hexanoyl chloride 23

J. Tanaka, Bull. Chem. Jpn. 1992, 65, 2851-2853.
Eine Lösung von 0.5 g (2.03 mmol) Carbonsäure 22 in 4 ml Benzol wird mit 362 mg (3.04 mmol, 1.5 equiv) Thionylchlorid (SOCl₂) versetzt und 2 h unter Rückfluß erhitzt. Man läßt abkühlen und destilliert das Lösungsmittel am Rotationsverdampfer ab. Um das überschüssige SOCl₂ aus der Reaktionsmischung zu entfernen, wird der Rückstand wieder mit Benzol versetzt und erneut abdestilliert. Man erhält 494 mg (1.865 mmol, 92%) des Säurechlorids 23. Dieses Rohprodukt wird ohne Aufreinigung und Charakterisierung weiter umgesetzt.J. Tanaka, Bull. Chem. Jpn. 1992, 65, 2851-2853.
A solution of 0.5 g (2.03 mmol) of carboxylic acid 22 in 4 ml of benzene is mixed with 362 mg (3.04 mmol, 1.5 equiv) of thionyl chloride (SOCl₂) 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 SOCl₂ from the reaction mixture, the residue is mixed again with benzene and distilled off again. 494 mg (1,865 mmol, 92%) of the acid chloride 23 are obtained. This crude product is reacted further without purification and characterization.

Darstellung von 3-[6-[(tert-Butyldimethylsilyl)oxy]-hexanoyl)-4-isopropyl­ oxazolldin-2-on 7Preparation of 3- [6 - [(tert-butyldimethylsilyl) oxy] hexanoyl) -4-isopropyl oxazolldin-2-one 7

A. Gonzalez, Synth. Comm. 1991, 21, 1353-1360.
Eine Lösung von 755 mg (5.845 mmol) (4S)-4-(1-Methylethyl)-2-oxazolidinon 24 in 8 ml THF wird auf -78°C gekühlt und tropfenweise mit 4.0 ml (6.43 mmol, 1.1 equiv) einer n-BuLi-Lösung (1.6 M in Hexan) versetzt. Anschließend wird bei -78°C innerhalb von 2 min eine Lösung von 1.703 g (6.43 mmol, 1.1 equiv) Säurechlorid 23 in 7 ml THF zugegeben. Man läßt auf RT erwärmen und versetzt mit 11 ml einer 1 M wäßrigen K₂CO₃-Lösung und läßt 15 min rühren. Es wird mit CH₂Cl₂ extrahiert, über MgSO₄ getrocknet und das Lösungsmittel am Rotationsverdampfer abdestilliert. Der Rückstand wird säulen-chromatographisch mit Pentan : Diethylether = 1 : 1 gereinigt. Man erhält 1.352 g (3.78 mmol) der Verbindung 7, entsprechend einer Ausbeute von 65%.
Allgemeine Daten: C₁₈H₃₅NO₄Si, FG = 357.56 g/mol
¹³C-NMR (100 MHz, CDCl₃): 173.22 (s), 154.02 (s), 63.26 (t), 62.94 (t), 58.32 (d), 35.47 (t), 32.52 (t), 28.32 (d), 25.92 (q), 25.36 (t), 24.18 (t), 18.29 (s), 17.92 (q), 14.61 (q), -5.34 (q). A. Gonzalez, Synth. Comm. 1991, 21, 1353-1360.
A solution of 755 mg (5,845 mmol) of (4S) -4- (1-methylethyl) -2-oxazolidinone 24 in 8 ml of THF is cooled to -78 ° C and added dropwise with 4.0 ml (6.43 mmol, 1.1 equiv) of a n -BuLi solution (1.6 M in hexane) added. A solution of 1,703 g (6.43 mmol, 1.1 equiv) of acid chloride 23 in 7 ml of THF is then added at -78 ° C. in the course of 2 min. The mixture is allowed to warm to RT and mixed with 11 ml of a 1 M aqueous K₂CO₃ solution and allowed to stir for 15 minutes. It is extracted with CH₂Cl₂, dried over MgSO₄ and the solvent is distilled off on a rotary evaporator. The residue is purified by column chromatography with pentane: diethyl ether = 1: 1. 1,352 g (3.78 mmol) of compound 7 are obtained, corresponding to a yield of 65%.
General data: C₁₈H₃₅NO₄Si, FG = 357.56 g / mol
13 C-NMR (100 MHz, CDCl₃): 173.22 (s), 154.02 (s), 63.26 (t), 62.94 (t), 58.32 (d), 35.47 (t), 32.52 (t), 28.32 (d), 25.92 (q), 25.36 (t), 24.18 (t), 18.29 (s), 17.92 (q), 14.61 (q), -5.34 (q).

Darstellung von 3-[6-[(tert-Butyldimethylsilyl)oxy]-2-methyl-hexanoyl]-4-iso­ propyl-oxazolidin-2-on 25Preparation of 3- [6 - [(tert-butyldimethylsilyl) oxy] -2-methyl-hexanoyl] -4-iso propyl-oxazolidin-2-one 25

D.A. Evans, A.E. Weber J. Am. Chem. Soc. 1986, 108, 6757-6761.
Es werden 1.231 ml (1.231 mmol, 1.1 equiv) einer 1 M Lösung von NaHMDS in THF auf -78°C gekühlt und tropfenweise mit einer auf 0°C gekühlten Lösung von 400 mg (1.119 mmol) Oxazolidinon 7 in 3.5 ml THF versetzt. Man läßt 30 min bei -78°C rühren, addiert 793 mg (5.593 mmol, 5 equiv) Methyljodid gelöst in 2 ml Tetrahydrofuran und läßt für 4 h bei -78°C rühren. Anschließend wird mit ges. NH₄Cl-Lösung gequencht, mit Diethylether extrahiert, über MgSO₄ getrocknet und eingeengt. Der Rückstand wird säulenchromatographisch mit Pentan : Diethylether = 2 : 1 gereinigt, wobei das in geringem Maße entstandene unerwünschte Diastereomer leicht abgetrennt werden kann. Man erhält 328 mg (0.917 mmol) des methylierten Produkts 25, entsprechend einer Ausbeute von 82%.
Allgemeine Daten: C₁₉H₃₇NO₄Si, FG = 371.59 g/mol
¹³C-NMR (100 MHz, CDCl₃): 177.13 (s), 153.60 (s), 63.13 (t), 62.95 (t), 58.38 (d), 37.63 (d), 32.83 (t), 32.78 (t), 28.37 (d), 25.92 (q), 23.50 (t), 18.29 (s), 17.89 (q), 17.76 (q), 14.63 (q), -5.33 (q).DA Evans, AE Weber J. Am. Chem. Soc. 1986, 108, 6757-6761.
1,231 ml (1,231 mmol, 1.1 equiv) of a 1 M solution of NaHMDS in THF are cooled to -78 ° C and a solution of 400 mg (1,119 mmol) oxazolidinone 7 in 3.5 ml THF cooled to 0 ° C is added dropwise. The mixture is stirred at -78 ° C. for 30 min, 793 mg (5,593 mmol, 5 equiv) methyl iodide dissolved in 2 ml of tetrahydrofuran are added and the mixture is stirred at -78 ° C. for 4 h. Then with sat. Quenched NH₄Cl solution, extracted with diethyl ether, dried over MgSO₄ and concentrated. The residue is purified by column chromatography with pentane: diethyl ether = 2: 1, and the undesired diastereomer which has formed to a small extent can easily be separated off. 328 mg (0.917 mmol) of the methylated product 25 are obtained, corresponding to a yield of 82%.
General data: C₁₉H₃₇NO₄Si, FG = 371.59 g / mol
13 C-NMR (100 MHz, CDCl₃): 177.13 (s), 153.60 (s), 63.13 (t), 62.95 (t), 58.38 (d), 37.63 (d), 32.83 (t), 32.78 (t), 28.37 (d), 25.92 (q), 23.50 (t), 18.29 (s), 17.89 (q), 17.76 (q), 14.63 (q), -5.33 (q).

Darstellung von 6-[(tert-Butyldimethylsilyl)oxy]-2-methyl-hexan-1-ol 26Preparation of 6 - [(tert-butyldimethylsilyl) oxy] -2-methyl-hexan-1-ol 26

D.A. Evans, A.E. Weber J. Am. Chem. Soc. 1986,108, 6757-6761.
Zu einer auf 0°C gekühlten Lösung von 168 mg (0.452 mmol) der Verbindung 25 in 3 ml Diethylether wird über einen Zeitraum von 40 min mit Hilfe einer Dosierpumpe 452 µl (0.452 mmol, 1 equiv) einer 1 M Lösung von Lithiumaluminiumhydrid (LAH) in Diethylether zugegeben. Falls sich DC-chroma­ tographisch noch Edukt nachweisen läßt, wird weitere LAH-Lösung zugetropft bis die Umsetzung vollständig ist. Es wird gequencht durch die Zugabe von 17 ml Wasser, 17 ml 15%iger wäßriger NaOH-Lösung und 52 ml Wasser. Anschließend wird über grobes Kieselgel mit Diethylether flashfiltriert und säulenchromatographisch mit Pentan : Diethylether = 1 : 1 gereinigt. Man erhält 94 mg (0.381 mmol) des Alkohols 26, entsprechend einer Ausbeute von 84%.
Allgemeine Daten: C₁₃H₃₀O₂Si, FG = 246.46 g/mol
¹³C-NMR (100 MHz, CDCl₃): 68.25 (t), 63.12 (t), 35.72 (d), 33.03 (t), 32.84 (t), 25.94 (q), 23.13 (t), 18.34 (s), 16.51 (q), -5.29 (q). DA Evans, AE Weber J. Am. Chem. Soc. 1986, 108, 6757-6761.
452 μl (0.452 mmol, 1 equiv) of a 1 M solution of lithium aluminum hydride (LAH.) Is added to a solution of 168 mg (0.452 mmol) of compound 25 in 3 ml of diethyl ether cooled to 0 ° C. over a period of 40 min using a metering pump ) added in diethyl ether. If DC-chromatographically still shows educt, further LAH solution is added dropwise until the reaction is complete. It is quenched by adding 17 ml of water, 17 ml of 15% aqueous NaOH solution and 52 ml of water. Then it is flash-filtered over coarse silica gel with diethyl ether and purified by column chromatography with pentane: diethyl ether = 1: 1. 94 mg (0.381 mmol) of alcohol 26 are obtained, corresponding to a yield of 84%.
General data: C₁₃H₃₀O₂Si, FG = 246.46 g / mol
13 C-NMR (100 MHz, CDCl₃): 68.25 (t), 63.12 (t), 35.72 (d), 33.03 (t), 32.84 (t), 25.94 (q), 23.13 (t), 18.34 (s), 16.51 (q), -5.29 (q).

Darstellung von 6-[(tert-Butyldimethylsilyl)oxy]-2-methyl-hexanal 4Preparation of 6 - [(tert-Butyldimethylsilyl) oxy] -2-methyl-hexanal 4

D.A. Evans, A.E. Weber J. Am. Chem. Soc. 1986,108, 6757-6761.
Eine Lösung aus 64 mg (0.505 mmol, 1.4 equiv) Oxalylchlorid in 2 ml CH₂Cl₂ wird auf -78°C gekühlt und 79 mg (1.011 mmol, 12.8 equiv) DMSO addiert. Nach 5 min wird eine Lösung aus 89 mg (0.361 mmol) des Alkohols 26 in 1 ml CH₂Cl₂ zugetropft. Man läßt 30 min bei -78°C rühren und addiert dann 161 mg (1.589 mmol, 4.4 equiv) NEt₃. Man ersetzt das -78°C Kältebad durch ein 30°C-Bad und läßt eine weitere Stunde rühren. Anschließend wird mit 5.2 ml Pentan verdünnt, mit 3.4 ml einer 1 M wäßrigen NaHSO₄-Lösung und 3 mal mit je 3.4 ml Wasser gewaschen, über MgSO₄ getrocknet und eingeengt. Der Rückstand wird mit Pentan : Diethylether = 2 : 1 säulenchromatographisch gereinigt. Man erhält 77 mg (0.315 mmol) des Aldehyds 4, entsprechend einer Ausbeute von 87%.
Allgemeine Daten: C₁₃H₂₈O₂Si, FG = 244.45 g/mol
¹³C-NMR (100 MHz, CDCl₃): 205.24 (d), 62.81 (t), 46.30 (d), 32.73 (t), 30.25 (t), 25.93 (q), 23.25 (t), 18.33 (s), 13.25 (q), -5.32 (q). DA Evans, AE Weber J. Am. Chem. Soc. 1986, 108, 6757-6761.
A solution of 64 mg (0.505 mmol, 1.4 equiv) oxalyl chloride in 2 ml CH₂Cl₂ is cooled to -78 ° C and 79 mg (1.011 mmol, 12.8 equiv) DMSO are added. After 5 min, a solution of 89 mg (0.361 mmol) of alcohol 26 in 1 ml of CH₂Cl₂ is added dropwise. The mixture is stirred at -78 ° C for 30 min and then added 161 mg (1,589 mmol, 4.4 equiv) NEt₃. The -78 ° C. cold bath is replaced by a 30 ° C. bath and the mixture is stirred for another hour. The mixture is then diluted with 5.2 ml of pentane, washed with 3.4 ml of a 1 M aqueous NaHSO₄ solution and 3 times with 3.4 ml of water each time, dried over MgSO₄ and concentrated. The residue is purified by column chromatography with pentane: diethyl ether = 2: 1. 77 mg (0.315 mmol) of aldehyde 4 are obtained, corresponding to a yield of 87%.
General data: C₁₃H₂₈O₂Si, FG = 244.45 g / mol
13 C-NMR (100 MHz, CDCl₃): 205.24 (d), 62.81 (t), 46.30 (d), 32.73 (t), 30.25 (t), 25.93 (q), 23.25 (t), 18.33 (s), 13.25 (q), -5.32 (q).

Schema 4 Scheme 4

Synthese von Segment 2 Synthesis of segment 2

Arbeitsvorschriften zur Synthese von Segment 8Working instructions for the synthesis of segment 8 3-[(t-Butyldimethylsilyl)oxy)-propanal 53 - [(t-Butyldimethylsilyl) oxy) propanal 5

Synthese durch Monosilylierung von 1,3-Propandiol und anschließende Swern- Oxidation des entstandenen 3-[(t-Butyldimethylsilyl)oxy]-1-propanols.
Allgemeine Daten: C₉H₂₀O₂Si; FG = 188.36; CAS-Nr. [89922-82-7]
¹³C-NMR (100 MHz, CDCl₃): d = 202.05 (d), 57.42 (t), 46.58 (t), 25.82 (q), 18.23 (s), -5.43 (q). Synthesis by monosilylation of 1,3-propanediol and subsequent Swern oxidation of the resulting 3 - [(t-butyldimethylsilyl) oxy] -1-propanol.
General data: C₉H₂₀O₂Si; FG = 188.36; CAS number [89922-82-7]
13 C-NMR (100 MHz, CDCl₃): d = 202.05 (d), 57.42 (t), 46.58 (t), 25.82 (q), 18.23 (s), -5.43 (q).

1-[(t-Butyldimethylsilyl)oxy]-3-hydroxy-4-methyl-4-penten 271 - [(t-Butyldimethylsilyl) oxy] -3-hydroxy-4-methyl-4-pentene 27

Zu 443 mg Mg-Drehspänen (18.2 mmol) und 1.5 ml abs. Tetrahydrofuran (THF) unter N₂ werden 0.2 ml 2-Brompropen gegeben, so daß die Grignardreaktion anspringt. Es wird unter gelegentlicher Kühlung eine Lösung von 1.7 ml 2-Brom­ propen (insgesamt 22 mmol) in 6 ml abs. Tetrahydrofuran langsam zugetropft, bis alle Magnesium-Späne gelöst sind. Zu der noch warmen Mischung wird eine Lösung von 2.862 g 5 (15.2 mmol) in 6 ml abs. THF getropft. Es wird 6 h bei RT gerührt. Danach gibt man 25 ml ges. NH₄Cl-Lsg. zu der Reaktionslösung und läßt 10 min rühren. Die Mischung wird in 30 ml ges. NH₄Cl-Lsg. gegossen und zweimal mit Ether extrahiert. Die vereinigten org. Phasen werden je einmal mit ges. NH₄Cl-Lsg. und ges. NaCl-Lsg. gewaschen. Man trocknet über MgSO₄, engt im Vakuum ein und reinigt flashchromatographisch (Ether : Pentan = 1 : 6).
Man erhält 2.749 g 27 (11.9 mmol; 79% d. Th.) als farbloses Öl.To 443 mg Mg turnings (18.2 mmol) and 1.5 ml abs. Tetrahydrofuran (THF) under N₂ are given 0.2 ml of 2-bromine propen, so that the Grignard reaction starts. With occasional cooling, a solution of 1.7 ml of 2-bromopropene (22 mmol in total) in 6 ml of abs. Tetrahydrofuran slowly added dropwise until all the magnesium shavings are dissolved. A solution of 2,862 g 5 (15.2 mmol) in 6 ml abs. THF dropped. The mixture is stirred at RT for 6 h. Then 25 ml of sat. NH₄Cl solution. to the reaction solution and allowed to stir for 10 min. The mixture is sat in 30 ml. NH₄Cl solution. poured and extracted twice with ether. The united org. Phases are recorded once with sat. NH₄Cl solution. and sat. NaCl solution. washed. It is dried over MgSO₄, concentrated in vacuo and purified by flash chromatography (ether: pentane = 1: 6).
2,749 g of 27 (11.9 mmol; 79% of theory) are obtained as a colorless oil.

Allgemeine Daten: C₁₂H₂₆O₂Si; FG = 230.43
¹³C-NMR (100 MHz, CDCl₃): 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).General data: C₁₂H₂₆O₂Si; FG = 230.43
13 C-NMR (100 MHz, CDCl₃): 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-[(t-Butyldimethylsilyl)oxy]-3-hydroxy-4-methyl-4-penten 11(S) -1 - [(t-butyldimethylsilyl) oxy] -3-hydroxy-4-methyl-4-pentene 11

Man löst 600 mg 2 (2.60 mmol) und 91.5 mg (-)-Diisopropyltartrat (0.391 mmol) unter N₂ in 10.4 ml abs. CH₂Cl₂ und versetzt mit 180 mg gepulvertem, frisch aktiviertem Molsieb. Als interner Standard für die GC werden 100 ml n-Decan dazugegeben. Man kühlt auf -20°C ab und gibt unter Rühren 74 mg Titan(IV)- isopropylat (0.260 mmol) dazu. Nach 30 min. wird ein aliquoter Teil von etwa 4 Tropfen entnommen und bei 0°C mit einer Mischung von je etwa 0.15 ml Ether und Eisen(II)-sulfat-Zitronensäure-Lösung (s. unten) aufgearbeitet. Die org. Phase dient als t₀-Probe für die GC. Man gibt 610 ml einer ca. 3 M-Lösung von t-Butylhydroperoxid in Isooctan (1.82 mmol) dazu. Die Reaktionsmischung wird im Kühlschrank bei -22°C aufbewahrt. Ein- bis zweimal täglich werden Proben entnommen und wie oben aufgearbeitet. Die jeweilige Konzentration von 11 wird gaschromatographisch bestimmt. Nach 118 h wird die Reaktion bei etwa 50%-iger Umsetzung von 27 abgebrochen. Bei -20°C wird eine frisch angesetzte, auf 0°C gekühlte Lösung von 3.3 g Eisen(II)-sulfat-heptahydrat und 1.1 g Zitronensäure­ monohydrat in 10 ml dest. Wasser dazugegeben. Nach 20 min kräftigem Rühren ohne weitere Kühlung wird die Mischung dreimal mit CH₂Cl₂ extrahiert. Die ges. org. Phasen werden auf ca. 10 ml eingeengt und bei 0°C 30 min. lang mit 3 ml NaOH-Lsg. (30% in ges. NaCl-Lsg) gerührt. Es wird wiederum dreimal mit CH₂Cl₂ extrahiert, und die vereinigten org. Phasen werden mit ges. NaCl-Lsg. gewaschen, über MgSO₄ getrocknet und eingeengt. 600 mg 2 (2.60 mmol) and 91.5 mg (-) - diisopropyl tartrate (0.391 mmol) are dissolved. under N₂ in 10.4 ml abs. CH₂Cl₂ and mixed with 180 mg powdered, fresh activated molecular sieve. 100 ml of n-decane are used as the internal standard for the GC added. The mixture is cooled to -20 ° C. and 74 mg of titanium (IV) are added with stirring. isopropylate (0.260 mmol). After 30 min. becomes an aliquot of about 4 drops removed and at 0 ° C with a mixture of about 0.15 ml ether and iron (II) sulfate-citric acid solution (see below) worked up. The org. phase serves as a t₀ sample for the GC. 610 ml of an approximately 3 M solution of t-Butyl hydroperoxide in isooctane (1.82 mmol). The reaction mixture is in Store refrigerator at -22 ° C. Samples are taken once or twice a day removed and worked up as above. The respective concentration of 11 will determined by gas chromatography. After 118 h the reaction becomes about 50% Implementation of 27 canceled. At -20 ° C is a freshly set, at 0 ° C chilled solution of 3.3 g iron (II) sulfate heptahydrate and 1.1 g citric acid monohydrate in 10 ml dist. Water added. After vigorous stirring for 20 min without further cooling, the mixture is extracted three times with CH₂Cl₂. The total org. Phases are concentrated to approx. 10 ml and 30 min at 0 ° C. long with 3 ml NaOH solution. (30% in saturated NaCl solution). It is again three times with CH₂Cl₂ extracted, and the combined org. Phases are with sat. NaCl solution. washed, dried over MgSO₄ and concentrated.  

Flashchromatographische Reinigung (Ether : Pentan = 1 : 6) liefert 274 mg 11 (1.19 mmol; 46% des Eduktes) als farbloses Öl.
Allgemeine Daten: C₁₂H₂₆O₂Si; FG = 230.43
(c = 1, CHCl₃), [a]D = -4.6°; ee = 90% (berechnet durch Integration der olefinischen ¹H-NMR-Signale sowie des ¹H-NMR-Signals der C-4-Methylprotonen der diastereomeren Reaktionsprodukte von 11 mit S(+)-a-Methoxy-a-trifluor-methyl­ phenylessigsäurechlorid, S(+)-MTPA-Cl).Flash chromatographic purification (ether: pentane = 1: 6) yields 274 mg 11 (1.19 mmol; 46% of the educt) as a colorless oil.
General data: C₁₂H₂₆O₂Si; FG = 230.43
(c = 1, CHCl₃), [a] D = -4.6 °; ee = 90% (calculated by integrating the olefinic 1 H-NMR signals and the 1 H-NMR signal of the C-4-methyl protons of the diastereomeric reaction products of 11 with S (+) - a-methoxy-a-trifluoromethyl phenylacetic acid chloride, S (+) - MTPA-Cl).

Die absolute Konfiguration des überwiegenden Enantiomers wurde nach der Methode von MOSHER durch Vergleich der ¹H-NMR-Spektren der Reaktionsprodukte von 11 mit S(+)-MTPA-Cl bzw. R(-)-MTPA-Cl bestimmt.The absolute configuration of the predominant enantiomer was determined according to the MOSHER's method by comparing the 1 H-NMR spectra of the Reaction products of 11 with S (+) - MTPA-Cl or R (-) - MTPA-Cl determined.

(S)-3-Benzyloxy-1-[(t-butyldimethylsilyl)oxy]-4-methyl-4-penten 28(S) -3-benzyloxy-1 - [(t-butyldimethylsilyl) oxy] -4-methyl-4-pentene 28

70 mg einer Suspension von 35% Kaliumhydrid in Mineralöl (0.609 mmol) werden unter N₂ mit 0.5 ml abs. THF versetzt und auf 0°C gekühlt. Man gibt 1.5 ml Benzylbromid (12.6 mmol) dazu. Unter Rühren wird eine Lösung von 117 mg 11 (0.508 mmol) und 3 mg Tetra-n-butylammoniumiodid (8 mmol) in 1 ml abs. THF dazugetropft. Nach 15 min läßt man auf RT erwärmen. Es wird 19 h gerührt, danach werden 8 ml ges. NH₄Cl-Lsg. eingespritzt. Die Mischung wird zweimal mit Ether extrahiert, die vereinigten org. Phasen werden zweimal mit ges. NaCl-Lsg. und einmal mit Wasser gewaschen und über MgSO₄ getrocknet. Nach dem Einengen am Rotationsverdampfer wird der Hauptteil des noch vorhandenen Benzylbromides bei RT im Hochvakuum abgezogen. Flashchromatographische Reinigung (Ether : Petrolether = 1 : 100) liefert 96 mg 28 (0.299 mmol; 59% d.Th.) als farbloses Öl.
Allgemeine Daten: C₁₉H₃₂O₂Si, FG = 320.54
¹³C-NMR (100 MHz, CDCl₃): d = 144.70 (s), 138.87 (s), 128.33 (d), 127.78 (d), 127.40 (d), 113.54 (t), 80.03 (d), 70.07 (t), 59.71 (t), 37.18 (t), 25.97 (q), 18.30 (s), 16.75 (q), -5.28 (q), -5.31 (q). 70 mg of a suspension of 35% potassium hydride in mineral oil (0.609 mmol) are treated with 0.5 ml of abs. THF added and cooled to 0 ° C. 1.5 ml of benzyl bromide (12.6 mmol) are added. A solution of 117 mg of 11 (0.508 mmol) and 3 mg of tetra-n-butylammonium iodide (8 mmol) in 1 ml of abs. THF added dropwise. After 15 min, the mixture is allowed to warm to RT. The mixture is stirred for 19 h, then 8 ml are sat. NH₄Cl solution. injected. The mixture is extracted twice with ether, the combined org. Phases are recorded twice with sat. NaCl solution. and washed once with water and dried over MgSO₄. After concentrating on a rotary evaporator, the main part of the benzyl bromide still present is removed at RT in a high vacuum. Flash chromatographic purification (ether: petroleum ether = 1: 100) yields 96 mg 28 (0.299 mmol; 59% of theory) as a colorless oil.
General data: C₁₉H₃₂O₂Si, FG = 320.54
13 C-NMR (100 MHz, CDCl₃): d = 144.70 (s), 138.87 (s), 128.33 (d), 127.78 (d), 127.40 (d), 113.54 (t), 80.03 (d), 70.07 (t ), 59.71 (t), 37.18 (t), 25.97 (q), 18.30 (s), 16.75 (q), -5.28 (q), -5.31 (q).

(S)-3-Benzyloxy-5-[(t-butyldimethylsilyl)oxy]-2-pentanon 9(S) -3-benzyloxy-5 - [(t-butyldimethylsilyl) oxy] -2-pentanone 9

Zu einer Mischung aus 1.5 ml THF und 1.5 ml Wasser werden 38 mg 28 (118 mmol) gegeben. 48 mg einer Lsg. von 2.5% OSO₄ in t-Butanol (4.7 mmol) werden mit 0.5 ml THF gemischt und dazugetropft. Es wird 5 min gerührt; dann werden 127 mg NalO₄ (590 mmol) dazugegeben. Nach 12 h kräftigem Rühren bei RT wird die Reaktionsmischung in 20 ml Ether gegossen und mit 5 ml Wasser verdünnt. Man extrahiert zweimal mit Ether, trocknet die vereinigten org. Phasen über MgSO₄ und engt ein. Flashchromatographische Reinigung (Ether : Pentan = 1 : 4) liefert 14 mg 9 (43.4 mmol; 37% d.Th.) als graubraunes Öl.
Allgemeine Daten: C₁₈H₃₀O₃Si; FG = 322.53
¹³C-NMR (100 MHz, CDCl₃): d = 211.00 (s), 137.67 (s), 128.51 (d), 127.94 (d), 127.90 (d), 82.00 (d), 72.59 (t), 58.68 (t), 35.23 (t), 25.94 (q), 25.68 (q), 18.30 (s), -5.38 (q), -5.43 (q).38 mg 28 (118 mmol) are added to a mixture of 1.5 ml THF and 1.5 ml water. 48 mg of a solution of 2.5% OSO₄ in t-butanol (4.7 mmol) are mixed with 0.5 ml THF and added dropwise. It is stirred for 5 min; then 127 mg of NalO₄ (590 mmol) are added. After vigorous stirring at RT for 12 h, the reaction mixture is poured into 20 ml of ether and diluted with 5 ml of water. It is extracted twice with ether, the combined org. Phases over MgSO₄ and concentrated. Flash chromatographic purification (ether: pentane = 1: 4) yields 14 mg 9 (43.4 mmol; 37% of theory) as a gray-brown oil.
General data: C₁₈H₃₀O₃Si; FG = 322.53
13 C-NMR (100 MHz, CDCl₃): d = 211.00 (s), 137.67 (s), 128.51 (d), 127.94 (d), 127.90 (d), 82.00 (d), 72.59 (t), 58.68 (t ), 35.23 (t), 25.94 (q), 25.68 (q), 18.30 (s), -5.38 (q), -5.43 (q).

4-Hydroxymethyl-2-methylthiazol 294-hydroxymethyl-2-methylthiazole 29

Die Verbindung 29 wird durch Ringschluß von L-Cystein-methylester-hydrochlorid mit Acetaldehyd, anschließender Dehydrierung über MnO₂ und Reduktion der Methylestergruppe durch LAH hergestellt.
Allgemeine Daten: C₅H₇NOS; FG = 129.19; CAS-Nr. [76632-23-0]
¹³C-NMR (50 MHz, CDCl₃): d = 167 (s), 156.0 (s), 114.4 (d), 60.5 (t), 19.0 (q).The compound 29 is prepared by ring closure of L-cysteine methyl ester hydrochloride with acetaldehyde, subsequent dehydrogenation over MnO₂ and reduction of the methyl ester group by LAH.
General data: C₅H₇NOS; FG = 129.19; CAS number [76632-23-0]
13 C-NMR (50 MHz, CDCl₃): d = 167 (s), 156.0 (s), 114.4 (d), 60.5 (t), 19.0 (q).

4-Brommethyl-2-methylthiazol 304-bromomethyl-2-methylthiazole 30

Man löst 60 mg 29 (0.464 mmol) in 1 ml abs. Ether und gibt unter Rühren 47 mg Triphenylphosphin (0.511 mmol) und 169 mg Tetrabrommethan (0.511 mmol) dazu. Nach 16 h Rühren (RT) wird der Niederschlag abfiltriert und mit Ether gewaschen. Das Filtrat wird eingeengt und flashchromato-graphisch gereinigt (Ether : Pentan = 1 : 5). Man erhält 33 mg 30 (0.172 mmol; 37% d.Th.) als helles bräunliches Öl.
Allgemeine Daten: C₅H₆BrNS; FG = 192.08
¹³C-NMR (100 MHz, CDCl₃): d = 166.91 (s), 151.63 (s), 117.25 (d), 27.11 (t), 19.25 (q). 60 mg of 29 (0.464 mmol) are dissolved in 1 ml of abs. Ether and with stirring 47 mg triphenylphosphine (0.511 mmol) and 169 mg tetrabromomethane (0.511 mmol). After stirring for 16 h (RT), the precipitate is filtered off and washed with ether. The filtrate is concentrated and purified by flash chromatography (ether: pentane = 1: 5). 33 mg of 30 (0.172 mmol; 37% of theory) are obtained as a light brownish oil.
General data: C₅H₆BrNS; FG = 192.08
13 C-NMR (100 MHz, CDCl₃): d = 166.91 (s), 151.63 (s), 117.25 (d), 27.11 (t), 19.25 (q).

Verbindung 10Connection 10

150 mg 1(0.78 mmol) und 300 ml Triethylphosphit (1.75 mmol) werden 1.5 Stunden lang auf 160°C erhitzt. Nach dem Abkühlen wird das überschüssige Triethylphosphit im Vakuum abdestilliert. Flashchromatographische Reinigung (Ether/Methanol = 19 : 1) liefert 173 mg 10 (89% d. Th.) als schwach gelbliches Öl.
¹³C-NMR (100 MHz, CDCl₃): d = 165.44 (s), 145.96 (ds, ²J(C,P)=8.2 Hz), 115.67 (dd, ³J(C,P)=7.4 Hz), 62.19 (dt, 2 C, ²J(C,P)=6.4 Hz), 29.35 (dt, ¹J(C,P)=141 Hz), 19.05 (q), 16.35 (dq, 2 C, ³J(C,P)=6.0 Hz).
(Anmerkung: Bei den zweifachen Angaben zur Signalmultiplizität bezieht sich das führende Zeichen auf die im Spektrum sichtbare durch C,P-Kopplung verursachte Multiplizität und das folgende Zeichen auf die durch C,H-Kopplung verursachte, im Standardspektrum unsichtbare Multiplizität.)150 mg 1 (0.78 mmol) and 300 ml triethyl phosphite (1.75 mmol) are heated to 160 ° C. for 1.5 hours. After cooling, the excess triethyl phosphite is distilled off in vacuo. Flash chromatographic purification (ether / methanol = 19: 1) yields 173 mg 10 (89% of theory) as a slightly yellowish oil.
13 C-NMR (100 MHz, CDCl₃): d = 165.44 (s), 145.96 (ds, ²J (C, P) = 8.2 Hz), 115.67 (dd, ³J (C, P) = 7.4 Hz), 62.19 (German , 2 C, ²J (C, P) = 6.4 Hz), 29.35 (dt, ¹J (C, P) = 141 Hz), 19.05 (q), 16.35 (dq, 2 C, ³J (C, P) = 6.0 Hz).
(Note: In the case of the double information on signal multiplicity, the leading symbol refers to the multiplicity visible in the spectrum caused by C, P coupling and the following symbol to the multiplicity invisible in the standard spectrum caused by C, H coupling.)

(S,4E)-3-Benzyloxy-1-(tert.butyldimethylsilyloxy)-4-methyl-5-(2-meth-yl-5-(2-methylthiazo- 4-yl)-pent-4-en 8(S, 4E) -3-benzyloxy-1- (tert-butyldimethylsilyloxy) -4-methyl-5- (2-meth-yl-5- (2-methylthiazo- 4-yl) -pent-4-en 8

Unter N₂ werden 33 mg 10 (132 mmol) in 2 ml abs. Tetrahydrofuran (THF) gelöst und auf -78°C gekühlt. Man tropft 78 ml n-BuLi-Lsg. (15% in Hexan; 125 mmol) dazu und läßt 45 min rühren. Anschließend wird bei -78°C eine Lösung von 35 mg Methylketon 9 (109 mmol) in 1 ml abs. THF dazugegeben. Nach langsamer Erwärmung auf RT läßt man noch 40 h rühren und gibt dann 10 ml ges. NH₄Cl-Lsg. zu der Reaktionsmischung. Es wird dreimal mit je 15 ml Ether extrahiert. Die vereinigten org. Phasen werden zweimal mit wenig Wasser und einmal mit ges. NaCl-Lsg. gewaschen. Nach dem Trocknen über MgSO₄ wird das Lösungsmittel am Rotationsverdampfer abdestilliert. Flashchromatographische Reinigung (Pentan-/Di­ chlormethan = 1 : 1, dann 1 : 2) liefert 17 mg (38% d. Th.) als farbloses Öl 8.
¹³C-NMR (100 MHz, CDCl₃): d = 164.4 (s), 152.90 (s), 139.74 (s), 138.84 (s), 128.33 (d, 2 C), 127.77 (d, 2 C), 127.41 (d), 121.33 (d), 115.67 (d), 82.00 (d), 70.30 (t), 59.69 (t), 37.58 (t), 25.98 (q, 3 C), 19.26 (q), 18.30 (s), 13.44 (q), -5.25 (q), -5.31 (q). 33 mg of 10 (132 mmol) in 2 ml of abs. Dissolved tetrahydrofuran (THF) and cooled to -78 ° C. 78 ml of n-BuLi solution are added dropwise. (15% in hexane; 125 mmol) and the mixture is stirred for 45 min. A solution of 35 mg of methyl ketone 9 (109 mmol) in 1 ml of abs. THF added. After slowly warming to RT, stirring is continued for 40 h and then 10 ml of sat. NH₄Cl solution. to the reaction mixture. It is extracted three times with 15 ml ether each. The united org. Phases are carried out twice with a little water and once with sat. NaCl solution. washed. After drying over MgSO₄, the solvent is distilled off on a rotary evaporator. Flash chromatographic purification (pentane / dichloromethane = 1: 1, then 1: 2) yields 17 mg (38% of theory) as a colorless oil 8.
13 C-NMR (100 MHz, CDCl₃): d = 164.4 (s), 152.90 (s), 139.74 (s), 138.84 (s), 128.33 (d, 2 C), 127.77 (d, 2 C), 127.41 ( d), 121.33 (d), 115.67 (d), 82.00 (d), 70.30 (t), 59.69 (t), 37.58 (t), 25.98 (q, 3 C), 19.26 (q), 18.30 (s) , 13.44 (q), -5.25 (q), -5.31 (q).

Darstellung von (4S,6S)-10-(tert.-Butyldimethylsilyoxy)-2-(2,2-dimethyl-[1,3]-dioxan-- 4-yl)-5-hydroxy-2,4,6-trimethyl-decan-3-on 80Preparation of (4S, 6S) -10- (tert-butyldimethylsilyoxy) -2- (2,2-dimethyl- [1,3] -dioxane-- 4-yl) -5-hydroxy-2,4,6-trimethyl-decan-3-one 80

Zu einer Lösung von 23 mg Diisopropylamin (0.227 mmol, leq.) in ml Tetrahydrofuran (THF) werden bei 0°C 142 ml (0.227 mmol, 1 Äquivalente) einer 1.6 M Lösung von n-BuLi in Hexan zugetropft und 30 Minuten bei 0°C gerührt, bevor dann auf -78°C heruntergekühlt wird. Nun werden 49 mg (0.227 mmol, 1 eq.) (S)-2-(2,2-dimethyl-[1,3]-dioxan-4-yl-2-methyl-pentan-3-on 3, gelöst in 1 ml THF langsam zugetropft. Die Lösung wird 35 min. bei -78°C gerührt. Anschließend werden 55 mg (0.224 mmol, 099 eq.) (S)-6-(tert.-Butyldimethylsilyoxy)-2-methyl­ hexanal 4 zugetropft und 1 h bei -78°C gerührt. Die Reaktion wird durch Zugabe von gesättigter NH₄Cl-Lösung gestoppt und auf RT erwärmt. Die wäßrige Phase wird mit Ether extrahiert, die vereinigten organischen Phasen über MgSO₄ getrocknet und das Lösungsmittel am Rotationsverdampfer abdestilliert. Der Rückstand wird säulenchromatographisch mit Pentan : Diethylether = 2 : 1 gereinigt. Man erhält 49 mg (0.107 mmol, 48%) (4S,6S)-10-(tert.-Butyldimethylsilyoxy)-2-(2,2-di­ methyl-[1,3] dioxan-4-yl)-5-hydroxy-2,4,6-trimethyl-decan-3-on 80 des Aldol­ produkts als farbloses Öl.
¹³C-NMR (50 MHz, C₆D₆): 98.50 (s), 74,93 (d), 74.65 (d), 63,25 (t), 59.70 (t), 51.56 (s), 41.70 (d), 35.82 (d), 33,67 (t), 33.05 (t), 30.01 (q), 26.17 (q), 25.37 (t), 23.32 (t), 21.53 (q), 19.01 (q), 18,69 (q), 18,51 (s), 15.63 (q), 9.63 (q).142 ml (0.227 mmol, 1 equivalent) of a 1.6 M solution of n-BuLi in hexane are added dropwise to a solution of 23 mg of diisopropylamine (0.227 mmol, leq.) In ml of tetrahydrofuran (THF) at 0 ° C and 30 minutes at 0 ° C before cooling down to -78 ° C. 49 mg (0.227 mmol, 1 eq.) (S) -2- (2,2-dimethyl- [1,3] -dioxan-4-yl-2-methyl-pentan-3-one 3, dissolved in 1 ml of THF is slowly added dropwise, and the solution is stirred for 35 minutes at -78 ° C. Then 55 mg (0.224 mmol, 099 eq.) (S) -6- (tert-butyldimethylsilyoxy) -2-methyl hexanal 4 are added dropwise and stirred for 1 h at -78 ° C. The reaction is stopped by adding saturated NH₄Cl solution and warmed to RT, 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 is purified by column chromatography with pentane: diethyl ether = 2: 1. 49 mg (0.107 mmol, 48%) (4S, 6S) -10- (tert-butyldimethylsilyoxy) -2- (2,2-di methyl- [1 , 3] dioxan-4-yl) -5-hydroxy-2,4,6-trimethyl-decan-3-one 80 of the aldol product as a colorless oil.
13 C-NMR (50 MHz, C₆D₆): 98.50 (s), 74.93 (d), 74.65 (d), 63.25 (t), 59.70 (t), 51.56 (s), 41.70 (d), 35.82 (d), 33.67 (t), 33.05 (t), 30.01 (q), 26.17 (q), 25.37 (t), 23.32 (t), 21.53 (q), 19.01 (q), 18.69 ( q), 18.51 (s), 15.63 (q), 9.63 (q).

Gemäß konventioneller Methoden wird der Benzylether hergestellt, um 81 zu erhalten; es können hier auch andere Hydroxylschutzgruppen verwendet werden.According to conventional methods, the benzyl ether is made to 81 receive; other hydroxyl protecting groups can also be used here.

Die Stufenfolge bis 86 ist aus dem Stand der Technik zu entnehmen, konventionelle Schutzgruppenchemie.The step sequence up to 86 can be found in the prior art, conventional Protecting group chemistry.

Schema 5 Scheme 5

Durch Oxidation, z. B. Pyridiniumdichromat wird die Carbonsäure 87 erhaltenBy oxidation, e.g. B. pyridinium dichromate, the carboxylic acid 87 is obtained

Die Veresterung zu 2 erfolgt hier beispielsweise mit DMAP/DCCl (Angew. Chem. 90, (1978), S. 556).The esterification to 2 takes place here, for example, with DMAP / DCCl (Angew. Chem. 90, (1978), p. 556).

Die Erfindung betrifft auch Stereoisomere der Verbindungen gemäß Ansprüche 1-5, wie diese üblicherweise innerhalb der Synthese anfallen. Ebenso Derivate der Verbindungen gemäß Ansprüche 1-5, die an den Hydroxyl-, Carbonyl- oder Carboxylgruppen andere Schutzgruppen tragen, die gemäß Methoden aus dem Stand der Technik herstellbar sind.The invention also relates to stereoisomers of the compounds according to Claims 1-5, as they usually arise within the synthesis. As well Derivatives of the compounds according to claims 1-5, which on the hydroxyl, carbonyl or Carboxyl groups carry other protecting groups, which according to methods the prior art can be produced.

Claims (6)

1. 2-(2,2-Dimethyl-[1,3]-dioxan-4-yl)-2-methyl-pentan-3-on 3.1. 2- (2,2-dimethyl- [1,3] -dioxan-4-yl) -2-methylpentan-3-one 3. 2. 6-[(tert.-Butyldimethylsilyl)oxy]-2-methyl-hexanal 4.2. 6 - [(tert-Butyldimethylsilyl) oxy] -2-methyl-hexanal 4. 3. (S,4E)-3-Benzyloxy-1-(tert.butyldimethylsilyloxy)-4-methyl-5-(2-ethy-l­ thiazol-4-yl)-pent-4-en 8.3. (S, 4E) -3-benzyloxy-1- (tert-butyldimethylsilyloxy) -4-methyl-5- (2-ethyl-l thiazol-4-yl) pent-4-ene 8. 4. (4S,6S)-10-(tert.Butyldimethylsilyloxy)-2-(2,2-dimethyl-[1,3]-dioxan--4-yl)- 5-hydroxy-2,4,6,-trimethyl-decan-3-on 80.4. (4S, 6S) -10- (tert-butyldimethylsilyloxy) -2- (2,2-dimethyl- [1,3] -dioxan - 4-yl) - 5-hydroxy-2,4,6, -trimethyl-decan-3-one 80. 5. 3S,6R,7S,8S)-7-Benzyloxy-3-(tert.-butyldimethylsilyloxy)-12 (tert.-butyldiphenylsilyloxy)-4,4,6,8-tetramethyl-5-oxo-dodecansäure- 87.5. 3S, 6R, 7S, 8S) -7-benzyloxy-3- (tert-butyldimethylsilyloxy) -12 (tert-Butyldiphenylsilyloxy) -4,4,6,8-tetramethyl-5-oxododecanoic acid-87. 6. Stereoisomere der Verbindungen gemäß Ansprüche 1-5.6. Stereoisomers of the compounds according to claims 1-5.
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US8076490B2 (en) 1996-11-18 2011-12-13 Helmholtz-Zentrum Fuer Infektionsforschung Gmbh Epothilones C, D, E, and F, preparation and compositions
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