DE19726627A1 - New intermediates for epothilone - Google Patents

New intermediates for epothilone

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Publication number
DE19726627A1
DE19726627A1 DE19726627A DE19726627A DE19726627A1 DE 19726627 A1 DE19726627 A1 DE 19726627A1 DE 19726627 A DE19726627 A DE 19726627A DE 19726627 A DE19726627 A DE 19726627A DE 19726627 A1 DE19726627 A1 DE 19726627A1
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Prior art keywords
alkyl
methyl
hydrogen
formula
compound
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DE19726627A
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German (de)
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Johann Prof Dr Mulzer
Andreas Dipl Chem Mantoulidis
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Compounds of formula (I), (II) and intermediates for them are new. R1 = H, 1-6C alkyl or benzyl; X = OH, halo, SO2Ph, SO2B or a group of formula (i); R2 = H or Me; B = 1-4C alkyl or 1-4C perfluoroalkyl; n = 0 or 1; Y = OH, Br or I; R3 = H or Me; R4 = chelatable protecting group; and R5 = 1-4C alkyl.

Description

Die Erfindung betrifft den in den Patentansprüchen gekennzeichneten Gegenstand, daß heißt Zwischenprodukte, Verfahren zu ihrer Herstellung und ihre Verwendung zur Herstellung von Epothilon A, Epothilon B oder deren Derivaten.The invention relates to the object characterized in the claims that means intermediates, processes for their preparation and their use for Production of epothilone A, epothilone B or their derivatives.

Es ist bekannt, daß die Naturstoffe Epothilon A (R = H) und Epothilon B (R = Methyl)
It is known that the natural substances epothilone A (R = H) and epothilone B (R = methyl)

fungizid und cytotoxisch wirken (DE 41 38 042 C2). Nach Hinweisen für eine in vitro Aktivität gegen Brust- und Darmtumorzelllinien erscheint diese Verbindungsklasse in besonderem Maße interessant für die Entwicklung eines Arzneimittels. Verschiedene Arbeitsgruppen beschäftigen sich daher mit der Synthese dieser makrocyclischen Verbindungen. Jede Arbeitsgruppe geht von anderen Bruchstücken des Makrocyclus aus, um die gewünschten Naturstoffe zu synthetisieren.act fungicidal and cytotoxic (DE 41 38 042 C2). For evidence of an in vitro Activity against breast and colon tumor cell lines appears in this class of compounds particularly interesting for the development of a drug. Various Working groups are therefore concerned with the synthesis of these macrocyclic Links. Each working group starts from different fragments of the macrocycle, to synthesize the desired natural products.

Es bestand daher die Aufgabe, geeignete Bruchstücke vor allem diastereomerenrein bereitzustellen, aus denen sich Epothilon A und Epothilon B und deren Derivate herstellen lassen.The task was therefore to find suitable fragments, especially diastereomerically pure To provide, which make up Epothilon A and Epothilon B and their derivatives have it made.

Es wurde nun gefunden, daß die Zwischenstufen der allgemeinen Formeln I
It has now been found that the intermediates of the general formulas I

worin R1 Wasserstoff, C1-C6-Alkyl, oder ein gegebenenfalls substituierter Benzylrest und
X OH, Halogen, -SO2Ph, -SO2-B oder
wherein R 1 is hydrogen, C 1 -C 6 alkyl, or an optionally substituted benzyl radical and
X OH, halogen, -SO 2 Ph, -SO 2 -B or

mit
R2 in der Bedeutung von Wasserstoff oder Methyl,
B in der Bedeutung von C1-C4-Alkyl oder C1-C4-Perfluoralkyl und
n in der Bedeutung von 0 oder 1 bedeuten,
und II
With
R 2 is hydrogen or methyl,
B in the meaning of C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl and
n is 0 or 1,
and II

worin
Y OH, Brom, Iod
R3 Wasserstoff oder Methyl,
R4 eine beliebige chelatisierungsfähige Schutzgruppe und
R5 C1-C4-Alkyl sein können,
geeignet sind für die Synthese von Epothilon A und Epothilon B und deren Derivaten.wherein
Y OH, bromine, iodine
R 3 is hydrogen or methyl,
R 4 is any protective group capable of chelation and
R 5 can be C 1 -C 4 alkyl,
are suitable for the synthesis of epothilone A and epothilone B and their derivatives.

Die Estergruppen R1 können beliebig gewählt werden. Sperrige, unter milden Reaktionsbedingungen entfernbare Ester wie zum Beispiel der tert.Butylester sind bevorzugt.The ester groups R 1 can be chosen arbitrarily. Bulky esters removable under mild reaction conditions such as the tert-butyl ester are preferred.

C1-C6-Alkyl bedeutet geradkettige oder verzweigte Alkylreste wie zum Beispiel Methyl, Ethyl, Propyl, Isopropyl, Butyl, Sekundärbutyl, Tertiärbutyl.C 1 -C 6 -alkyl means straight-chain or branched alkyl radicals such as, for example, methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl.

Als substituierter Benzylrest R1 kommen z. B. p-Methoxybenzyl, 2,4-Dimethoxybenzyl in Frage.As a substituted benzyl radical R 1 z. B. p-methoxybenzyl, 2,4-dimethoxybenzyl in question.

Halogen bedeutet Fluor, Chlor, Brom Jod, wobei Brom und Jod bevorzugt sind.Halogen means fluorine, chlorine, bromine, iodine, with bromine and iodine being preferred.

Der Phenylring des Phenylsulfonrestes in der Bedeutung von X kann gegebenenfalls beliebige Substituenten tragen zum Beispiel CH3, CF3.The phenyl ring of the phenylsulfone radical in the meaning of X can optionally carry any substituents, for example CH 3 , CF 3 .

Unter C1-C4-Perfluoralkyl sind geradkettige oder verzweigte vollständig fluorierte Alkylreste wie zum Beispiel CF3, C2F5, C3F7, C4F9 zu verstehen. C 1 -C 4 perfluoroalkyl is to be understood as straight-chain or branched, completely fluorinated alkyl radicals such as, for example, CF 3 , C 2 F 5 , C 3 F 7 , C 4 F 9 .

Unter einer beliebigen chelatisierungsfähigen Schutzgruppe R4 und R7 sind zum Beispiel p-Methoxybenzyl, Trimethylsilyl, Tri-isopropylsilyl (TIPS) oder andere Silylether, sowie Benzyl, Tetrahydropyranyl, Methoxymethyl, SEM, Benzoyl, Acetyl zu verstehen. Besitzen zwei nebeneinanderstehende Alkoholfunktionen den Rest R7 als Schutzgruppe, so kann dieser auch eine p-Methoxyphenylmethylengruppe sein, die an beide Sauerstoffatome gleichzeitig gebunden ist.Any protective groups R 4 and R 7 which can be chelated are, for example, p-methoxybenzyl, trimethylsilyl, tri-isopropylsilyl (TIPS) or other silyl ethers, and also benzyl, tetrahydropyranyl, methoxymethyl, SEM, benzoyl, acetyl. If two adjacent alcohol functions have the radical R 7 as a protective group, this can also be a p-methoxyphenylmethylene group which is bonded to both oxygen atoms at the same time.

C1-C4-Alkyl bedeutet Methyl, Ethyl, Propyl, Isopropyl, Butyl, Sekundärbutyl, Tertiärbutyl.C 1 -C 4 alkyl means methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl.

Die Reste R8, R9, und R10 können gleich oder verschieden sein und C1-C4-Alkyl oder Phenyl bedeuten.The radicals R 8 , R 9 and R 10 may be the same or different and denote C 1 -C 4 alkyl or phenyl.

Die Zwischenstufe der allgemeinen Formel I
The intermediate of general formula I.

kann diastereomerenrein hergestellt werden.can be made diastereomerically pure.

In Schema 1 ist die Herstellung beispielhaft für R1 = Wasserstoff und X = OH dargestellt, wobei die Alkoholfunktionen des Endproduktes noch Schutzgruppen tragen, die nach bekannten Methoden abspaltbar sind.
In Scheme 1, the preparation is exemplified for R 1 = hydrogen and X = OH, the alcohol functions of the end product still bearing protective groups which can be eliminated by known methods.

Die Herstellung der Verbindung der Formel I beginnt mit der Reduktion von Methyl-3- hydroxy-(2S)-methylpropionat, das nach Schützen der Hydroxygruppe (a) mit p- Methoxy-benzyl-2,2,2-trichloracetimidat(PMBTCAI) mit Diisopropylaluminiumhydrid (b) zum Alkohol umgesetzt wird. Swern-Oxidation (c) führt zum Aldehyd, der ohne Reinigung weiter umgesetzt wird. Unter den üblichen Bedingungen wird von 2,2- Dimethyl-1-hexen-4-on bei -90°C innerhalb von 30 min. mit Lithiumdiisopropylamid (d) das Lithiumenolat erzeugt, zu dem der ungereinigte Aldehyd in Tetrahydrofuran langsam zugegeben wird. Die Syn-Aldol-Produkte entstehen als Diastereomerengemisch in einem Verhältnis von 79 : 21 und können aufgetrennt werden. Das eingesetzte Keton, 2,2- Dimethyl-1-hexen-4-on, wird leicht durch Reaktion der aus Prenylchlorid mit Magnesium erhaltenen Grignardverbindung mit Propionylchlorid erhalten. Die sekundäre Alkoholfunktion des Syn-Aldol-Hauptproduktes wird als Benzylidenacetal (e) geschützt. Dieses wird unter Zugabe von aktiviertem Molekularsieb und Dichlordicyanobenzochinon unter wasserfreien Bedingungen erhalten. Ozonolyse (f) der terminalen Vinylgruppe setzt den Aldehyd frei, der einer Allylborierung unterworfen wird, bei der nach oxidativer Aufarbeitung mit 5 Äquivalenten Natriumhydroperoxid (g) ein Diastereomerengemisch der beiden Alkohole im Verhältnis von 81 : 19 erhalten werden. Nach Diastereomerentrennung mit HPLC wird die Hydroxygruppe als Tertiärbutyldimethylsilylether durch Umsetzung mit Tertiärbutyldimethylsilyltriflat, 2,6- Lutidin bei 0°C in Methylenchlorid geschützt (h). Ozonolyse der Doppelbindung bei -78°C unter Aufwärmen auf Raumtemperatur in Methylenchlorid/Methanol 20 : 1 und Aufarbeitung mit Triphenylphosphin (i) und Pinnick-Oxidation des Aldehyds mit Natriumchlorit, Natriumdihydrogenphosphat, 2,3-dimethyl-but-2-en in 3 Stunden in Tertiärbutanol/Wasser-Gemisch (k) führt zur Carbonsäure. Es wird die Zwischenstufe der Formel I erhalten, worin zwei Hydroxygruppen als cyclisches Acetal und die b- Hydroxygruppe als tert.Butyldimethylsilylether geschützt sind. Beide Schutzgruppen lassen sich bei Bedarf auf literaturbekannte Weise entfernen.The preparation of the compound of formula I begins with the reduction of methyl 3- hydroxy- (2S) -methylpropionate, which after protecting the hydroxy group (a) with p- Methoxy-benzyl-2,2,2-trichloroacetimidate (PMBTCAI) with diisopropyl aluminum hydride (b) is converted to alcohol. Swern oxidation (c) leads to the aldehyde without Cleaning is implemented further. Under the usual conditions from 2.2- Dimethyl-1-hexen-4-one at -90 ° C within 30 min. with lithium diisopropylamide (d) produces the lithium enolate to which the unpurified aldehyde in tetrahydrofuran slowly is added. The Syn-Aldol products are created as a mixture of diastereomers in one Ratio of 79:21 and can be separated. The ketone used, 2.2- Dimethyl-1-hexen-4-one, is easily made by reacting the prenyl chloride with magnesium obtained Grignard compound with propionyl chloride. The secondary Alcohol function of the main syn-aldol product is protected as benzylidene acetal (s). This is done with the addition of activated molecular sieve and dichlorodicyanobenzoquinone obtained under anhydrous conditions. Ozonolysis (f) of the terminal vinyl group sets free the aldehyde, which is subjected to allylboration, in the case of oxidative Working up with 5 equivalents of sodium hydroperoxide (g) a mixture of diastereomers of the two alcohols can be obtained in a ratio of 81:19. After Diastereomer separation using HPLC is called the hydroxy group Tertiary butyldimethylsilyl ether by reaction with tertiary butyldimethylsilyl triflate, 2,6- Lutidine protected at 0 ° C in methylene chloride (h). Double bond ozonolysis -78 ° C while warming to room temperature in methylene chloride / methanol 20: 1 and Work up with triphenylphosphine (i) and Pinnick oxidation of the aldehyde with Sodium chlorite, sodium dihydrogen phosphate, 2,3-dimethyl-but-2-ene in 3 hours Tertiary butanol / water mixture (k) leads to carboxylic acid. It becomes the intermediate stage of the Obtained formula I, in which two hydroxyl groups as cyclic acetal and the b- Hydroxy group are protected as tert-butyldimethylsilyl ether. Both protection groups can be removed if necessary in a manner known from the literature.

Die nachfolgenden Beispiele dienen der näheren Erläuterung der Erfin­ dungsgegenstandes, ohne ihn auf diese beschränken zu wollen.The following examples serve to explain the Erfin in more detail subject matter, without wishing to restrict it to these.

Präperative MethodenPreparative methods

Alle Umsetzungen metallorganischer Reagenzien und alle Reaktionen in absoluten Lösemitteln werden unter Luft- und Feuchtigkeitsausschluß durchgeführt. Die verwendeten Glasapparaturen werden vor Versuchsbeginn mehrmals im Ölpumpen­ vakuum ausgeheizt und mit getrocknetem Argon der Firma Linde belüftet. Wenn nicht anders angegeben, werden sämtliche Reaktionsansätze magnetisch gerührt.All reactions of organometallic reagents and all reactions in absolute Solvents are carried out in the absence of air and moisture. The Glass devices are used several times before starting the test in oil pumps  heated under vacuum and aerated with dried argon from Linde. Unless otherwise stated, all reaction batches are stirred magnetically.

Methylenchlorid wird über eine basische Aluminiumoxidsäule der Aktivitätsstufe I (Woelm) getrocknet. Diethylether wird nach Vortrocknung auf einer basischen Aluminiumoxidsäule über eine 8 : 1 Natrium/Kalium-Legierung refluxiert bis zur stabilen Blaufärbung des Benzophenon-Indikators und vor der Verwendung frisch abdestilliert. Das Tetrahydrofuran (THF) wird über KOH vorgetrocknet, über eine mit basischem Aluminiumoxid beschickte Säule filtriert und anschließend über Kalium mit Triphenylmethan als Indikator destilliert.Methylene chloride is over a basic alumina column of activity level I (Woelm) dried. After predrying, diethyl ether is based on a basic Aluminum oxide column refluxed over an 8: 1 sodium / potassium alloy to a stable one Blue color of the benzophenone indicator and freshly distilled off before use. The tetrahydrofuran (THF) is predried over KOH, over one with basic Filtered alumina column and then with potassium Distilled triphenylmethane as an indicator.

Der Essigsäureethylester (EE) wird nach Vortrocknung über Calciumchlorid ebenso wie Hexan (Hex) vor der Verwendung zur Säulenchromatographie am Rotationsverdampfer abdestilliert.The ethyl acetate (EE) is after predrying over calcium chloride as well as hexane (hex) before use for column chromatography on Distilled off rotary evaporator.

Chromatographische VerfahrenChromatographic procedures

Sämtliche Reaktionen werden durch Dünnschichtchromatographie (DC) auf Kieselgel-60- Alufolien mit UV-Indikator F254 der Firma Merck verfolgt. Als Laufmittel werden zumeist Lösemittelgemische aus Hexan (Hex) und Essigsäureethylester (EE) verwendet. Zum Sichtbarmachen nicht UV-aktiver Substanzen bewährt sich meist Anisaldehyd/ Eisessig/Schwefelsäure (1 : 100 : 1) als Standard-Tauchreagenz.All reactions are followed by thin layer chromatography (TLC) on silica gel 60 aluminum foil with Merck UV indicator F 254 . Solvent mixtures of hexane (hex) and ethyl acetate (EE) are mostly used as eluents. To make non-UV-active substances visible, anisaldehyde / glacial acetic acid / sulfuric acid (1: 100: 1) usually works as a standard immersion reagent.

Die präperative Säulenchromatographie wird an Kieselgel-60 der Firma Merck (0,04-0,063 mm, 230-400 mesh) durchgeführt, wobei als Eluens Lösemittelgemische aus Hexan (Hex) und Essigsäureethylester (EE) bzw. Diisopropylether dienen.The preparative column chromatography is carried out on silica gel 60 from Merck (0.04-0.063 mm, 230-400 mesh), using solvent mixtures as the eluent Hexane (hex) and ethyl acetate (EE) or diisopropyl ether are used.

Im analytischen, wie auch im präperativen Maßstab werden die hochdruckflüssig­ keitschromatographischen Trennungen (HPLC) auf Modulsystemen der Firmen Knauer (Pumpe 64, UV- und RI-Detektoren, Säulen und Schreiber), Waters/Millipore (Injek­ tionssystem U6K9) und Milton-Roy (Integrator CI-10) durchgeführt. Für die analytische HPLC wird zumeist eine Knauer-Säule (4.250 mm) mit 5 µm Nucleosil und für die präperative HPLC eine Säule (16.250 mm, 32.250 mm bzw. 64.300 mm) mit 7 µm oder 5 µm Nucleosil 50 verwendet.They become highly pressurized on an analytical as well as a preparative scale time chromatographic separations (HPLC) on module systems from Knauer (Pump 64, UV and RI detectors, columns and recorders), Waters / Millipore (Injek tion system U6K9) and Milton-Roy (integrator CI-10). For the analytical HPLC is usually a Knauer column (4,250 mm) with 5 µm nucleosil and for the preparative HPLC a column (16.250 mm, 32.250 mm or 64.300 mm) with 7 µm or 5 µm Nucleosil 50 used.

FärbereagenzienStaining reagents

Färbereagenz I (FI): 1 g Cer(IV)sulfat in 10 mL konz. Schwefelsäure und 90 mL Wasser liefert mit den meisten reduzierbaren Verbindungen intensiv blaue Farbreaktion beim Trocknen. Coloring reagent I (FI): 1 g cerium (IV) sulfate in 10 mL conc. Sulfuric acid and 90 mL With most reducible compounds, water provides an intense blue color reaction when drying.  

Färbereagenz II (F II): Eine 10%ige ethanolische Lösung von Molybdatophosphorsäure stellt ein weiteres Tauchreagenz zum Nachweis ungesättigter und reduzierbarer Verbindungen dar. Im Unterschied zum Färbereagenz I zeigt das Molybdat-Färbereagenz, speziell auf einige Funktionalitäten ansprechend, ein breiteres Farbspektrum bei praktisch gleicher Zuverlässigkeit.Coloring Reagent II (F II): A 10% ethanol solution of Molybdatophosphoric acid is another immersion reagent for the detection of unsaturated and reducible compounds. In contrast to dye reagent I, this shows Molybdate dye reagent, especially responsive to some functionalities, a wider one Color spectrum with practically the same reliability.

Färbereagenz III (F III): 1 mL Anisaldehyd in 100 mL Ethanol und 2 mL konz. Schwefelsäure stellt ein äußerst empfindliches Färbereagenz dar, daß zudem auch das wohl breiteste Farbspektrum zeigt.Staining reagent III (F III): 1 mL anisaldehyde in 100 mL ethanol and 2 mL conc. Sulfuric acid is an extremely sensitive dye reagent that also probably shows the widest color spectrum.

Färbereagenz IV (F IV): Das Vanillin-Tauchbadreagenz ist ähnlich empfindlich, wie das Anisaldehyd-Färbereagenz und zeigt wie dieses ein nahezu breites Farbspektrum.Coloring Reagent IV (F IV): The vanillin dip reagent is as sensitive as the anisaldehyde staining reagent and, like this, shows an almost wide range of colors.

Färbereagenz V (F V): 1 g 2,4-Dinitrophenylhydrazin in 25 mL Ethanol, 8 mL Wasser und 5 mL konz. Schwefelsäure stellt ein hervorragendes, selektiv schon ohne Erwärmung auf Aldehyde und etwas langsamer auf Ketone ansprechendes, Tauchreagenz dar.Staining reagent V (F V): 1 g of 2,4-dinitrophenylhydrazine in 25 mL ethanol, 8 mL Water and 5 mL conc. Sulfuric acid provides an excellent, selective already without Warming up to aldehydes and a slightly slower ketone-sensitive immersion reagent represents.

Färbereagenz VI (F VI): Eine 0.5%ige wässerige Lösung von Kaliumpermanganat zeigt durch Entfärbung oxidierbare Gruppen an, wobei ungesättigte, nicht aromatische Struktureinheiten spontan ohne Erwärmung reagieren. Coloring Reagent VI (F VI): A 0.5% aqueous solution of potassium permanganate indicates groups that can be oxidized by decolorization, whereby unsaturated, non-aromatic Structural units react spontaneously without heating.  

Spektroskopische Verfahren und allgemeine AnalytikSpectroscopic methods and general analysis NMR-SpektroskopieNMR spectroscopy

Die 1H-NMR-Spektren werden mit einem AC 250, AM 270 oder AMX 500 Spektrometer der Firma Bruker mit den Substanzen als Lösung in deuterierten Lösemitteln und Tetramethylsilan als internem Standard aufgenommen. Die Auswertung der Spektren erfolgt nach den Regeln erster Ordnung. Ist eine auftretende Signalmultiplizität damit nicht zu erklären, erfolgt die Angabe des beobachteten Liniensatzes. Zur Bestimmung der Stereochemie wird die NOE-Spektroskopie (Nuclear Overhauser Effect) verwendet.The 1 H-NMR spectra are recorded with an AC 250, AM 270 or AMX 500 spectrometer from Bruker with the substances as a solution in deuterated solvents and tetramethylsilane as an internal standard. The spectra are evaluated according to the rules of the first order. If an occurring signal multiplicity cannot be explained with this, the observed line set is specified. To determine the stereochemistry, NOE spectroscopy (Nuclear Overhauser Effect) is used.

Zur Charakterisierung der Signale werden folgende Abkürzungen verwendet: s (Singulett), d (Dublett), dd (Doppeldublett), ddd (6-Liniensystem bei zwei gleichen Kopplungskonstanten bzw. ein 8-Liniensystem bei drei verschiedenen Kopplungs­ konstanten), t (Triplett), q (Quartett), quint (Quintett), sext (Sextett), sept (Septett), m (Multiplett), mc (zentriertes Multiplett), br (breit) und v (verdecktes Signal).The following abbreviations are used to characterize the signals: s (Singlet), d (doublet), dd (double doublet), ddd (6-line system for two of the same Coupling constants or an 8-line system with three different coupling constant), t (triplet), q (quartet), quint (quintet), sext (sextet), sept (septet), m (Multiplet), mc (centered multiplet), br (wide) and v (hidden signal).

Die 13C-NMR-Spektren werden mit einem AC 250 der Firma Bruker mit CDCl3- Signal bei 77,0 ppm als internem Standard vermessen, wobei die Protonenresonanzen breitbandentkoppelt werden.The 13 C-NMR spectra are measured with an AC 250 from Bruker with CDCl 3 signal at 77.0 ppm as the internal standard, the proton resonances being decoupled broadband.

Herstellungsvorschrift 1Manufacturing instructions 1 Darstellung von 4,4-Dimethyl-hex-5-en-3-onPreparation of 4,4-dimethyl-hex-5-en-3-one

In einem Dreihalsrundkolben mit Innenthermometer und Teflon-Septum-Weiterleitung werden 17 g Magnesiumspäne in 100 mL abs. THF vorgelegt. Die Oberfläche des Mg wird durch einige Kriställchen Iod aktiviert und noch einige Tropfen Chloro-3-Methyl- But-2-en bei Raumtemperatur zugegeben.In a three-necked round bottom flask with an internal thermometer and Teflon septum transfer 17 g magnesium shavings in 100 mL abs. Submitted to THF. The surface of the Mg  is activated by a few crystals of iodine and a few more drops of chloro-3-methyl But-2-ene added at room temperature.

Nach 10 min wird die Lösung auf -15°C abgekühlt und 27 mL 1-Chlor-3-methyl­ but-2-en (239 mmol) in 100 mL abs. THF über einen Zeitraum von etwa 4 h zugetropft.After 10 min the solution is cooled to -15 ° C and 27 mL 1-chloro-3-methyl but-2-ene (239 mmol) in 100 mL abs. THF was added dropwise over a period of about 4 h.

Die Reaktionslösung wird auf Raumtemperatur erwärmen gelassen und 30 min nachgerührt. Die fertige Grignard-Lsg. wird vom Magnesiumrest abdekantierend in einen Tropftrichter des zweiten Reaktionsgefäßes durch Argonüberdruck transferiert. Nun wird die Grignard-Lösung zu 41.7 mL (476 mmol) Propansäurechlorid in 100 mL abs. THF bei -78°C über ca. 2 h zugetropft. Die wird Lösung auf Raumtemperatur erwärmen gelassen, 1 h nachgerührt und schließlich auf 500 mL Eiswasser gegossen.The reaction solution is allowed to warm to room temperature and 30 min stirred. The finished Grignard solution. is decanted from the magnesium residue into one Dropping funnel of the second reaction vessel transferred by argon overpressure. Well now the Grignard solution to 41.7 mL (476 mmol) propanoic acid chloride in 100 mL abs. THF added dropwise at -78 ° C for about 2 h. The solution will warm to room temperature left, stirred for 1 h and finally poured onto 500 mL ice water.

Die Phasen werden getrennt, die wäßrige noch zweimal mit Diethylether extrahiert,die vereinigten organischen Phasen mit 600 mL 2M NaOH und 300 mL Brine gewaschen und über Magnesiumsulfat getrocknet.The phases are separated, the aqueous two more times with diethyl ether extracted, the combined organic phases with 600 mL 2M NaOH and 300 mL brine washed and dried over magnesium sulfate.

Nach Entfernung des Solvens am Rotationsverdampfer wird das verbleibende Rohprodukt über eine Vigreux-Kolonne im Wasserstrahlvakuum bei ca. 35°C destilliert (Lit.: 73°C bei 40 Torr). Es wurden 22.45 g (74.6%) sauberes Produkt, als klare Lösung, erhalten.
After removing the solvent on a rotary evaporator, the remaining crude product is distilled through a Vigreux column in a water jet vacuum at approx. 35 ° C (lit .: 73 ° C at 40 torr). 22.45 g (74.6%) of clean product, as a clear solution, were obtained.

1H-NMR (250 MHz, CDCl3) für das Keton: δ in ppm =
1.01 (t, J = 7.5 Hz, 3H, H-1); 1.23 (s, 6H, H-3); 2.49 (q, J = 14.5, 7.25 Hz, 2H, H-2); 5.10 (dd, J = 3.2, 0.8 Hz, 1H, H-5); 5.16 (dd, J = 3.1, 0.8 Hz, 1H, H-5); 5.93 (dd, J = 17.5, 10.6 Hz, 1H, H-4).
 1 H-NMR (250 MHz, CDCl 3 ) for the ketone: δ in ppm =
1.01 (t, J = 7.5 Hz, 3H, H-1); 1.23 (s, 6H, H-3); 2.49 (q, J = 14.5, 7.25 Hz, 2H, H-2); 5.10 (dd, J = 3.2, 0.8 Hz, 1H, H-5); 5.16 (dd, J = 3.1, 0.8 Hz, 1H, H-5); 5.93 (dd, J = 17.5, 10.6 Hz, 1H, H-4).

13C-NMR (62.5 MHz, CDCl3): δ in ppm =
8.0; 23.4; 30.4; 50.5; 113.8; 142.6; 213.5.
 13 C-NMR (62.5 MHz, CDCl 3 ): δ in ppm =
8.0; 23.4; 30.4; 50.5; 113.8; 142.6; 213.5.

IR (KBr-Film): ν in cm-1 =
3087 m; 2976 vs; 2938 s; 2879 m; 1840 w; 1712 vs; 1634 m; 1463 m; 1414 m; 1378 m; 1363 m; 1343 m; 1204 w; 1173 w; 1100 s; 1048 w; 1021 m; 1002 m; 972 m; 919 s; 823 w; 806 w; 681 m.
IR (KBr film): ν in cm -1 =
3087 m; 2976 vs; 2938 s; 2879 m; 1840 w; 1712 vs; 1634 m; 1463 m; 1414 m; 1378 m; 1363 m; 1343 m; 1204 w; 1173 w; 1100 s; 1048 w; 1021 m; 1002 m; 972 m; 919 s; 823 w; 806 w; 681 m.

MS (EI, 70 eV, 40°C): m/e =
127[M+H]; 126 [M⁺]; 90; 73; 70; 69; 66; 57.
MS (EI, 70 eV, 40 ° C): m / e =
127 [M + H]; 126 [M⁺]; 90; 73; 70; 69; 66; 57.

C8H14O: (M= 126 g.mol-1) C 8 H 14 O: (M = 126 g.mol -1 )

Beispiel 1example 1 Darstellung von (+)-(2S)-[3-[(4-methoxyphenyl)methoxy]-2-methyl] propansäure-methylesterPreparation of (+) - (2S) - [3 - [(4-methoxyphenyl) methoxy] -2-methyl] methyl propanoate

Zu 0.4 g (10 mmol; 60%ige Form) Natriumhydrid in 50 mL abs. Diethylether werden bei Raumtemperatur unter Argon langsam 13.8 g (100 mmol) para-Methoxybenzylalkohol in 30 mL abs. Diethylether gelöst, zugegeben und noch 30 min bei Raumtemperatur gerührt, wobei sich die Lösung gelblich einfärbt.To 0.4 g (10 mmol; 60% form) sodium hydride in 50 mL abs. Diethyl ether are used in Room temperature under argon slowly 13.8 g (100 mmol) para-methoxybenzyl alcohol in 30 mL abs. Dissolved diethyl ether, added and stirred for a further 30 min at room temperature, whereby the solution turns yellowish.

Die Reaktionslösung wird auf ca. -5°C abgekühlt und dann langsam mit 10.13 mL (100 mmol) Trichloracetonitril versetzt und über 4 h auf Raumtemperatur erwärmen gelassen, wobei sich die Lösung trüb orange-braun verfärbt. Die rohe Lösung wird am Rotationsverdampfer konzentriert, mit 100 mL einer Hex/MeOH-Lsg. (98 : 2) versetzt und die ausgefallenen Salze über eine Kieselgel/Celite beschickte G3-Fritte filtriert. Die Salze werden noch dreimal mit ca. 50 mL der Hex/MeOH-Lsg. nachgewaschen und einrotiert.The reaction solution is cooled to about -5 ° C and then slowly with 10.13 mL (100 mmol) trichloroacetonitrile are added and the mixture is warmed to room temperature over 4 h left, whereby the solution turns cloudy orange-brown. The crude solution is on Rotary evaporator concentrated, with 100 mL of a hex / MeOH solution. (98: 2) offset and the precipitated salts are filtered through a G3 frit charged with silica gel / Celite. The salts are three more times with approx. 50 mL of the Hex / MeOH solution. washed and evaporated.

Zu einer Lösung des Rohimidats in 100 mL abs. CH2Cl2 werden 6.66 g (56.38 mmol) (S)-Roche'säuremethylester zugegeben und auf ca. -5°C abgekühlt. Bei dieser Temperatur werden unter kräftigem Rühren 5 Tropfen Trifluormethansulfonsäure (kat. Menge) vorsichtig zugetropft, wobei sofort Trichloracetimidatsalze auszufallen beginnen.To a solution of the raw imidate in 100 mL abs. CH 2 Cl 2 , 6.66 g (56.38 mmol) of (S) -rochoic acid methyl ester are added and the mixture is cooled to about -5 ° C. At this temperature, 5 drops of trifluoromethanesulfonic acid (cat. Amount) are carefully added dropwise, with vigorous stirring, trichloroacetimidate salts immediately starting to precipitate out.

Die Lösung wird über Nacht auftauen gelassen, die ausgefallenen Salze über eine Kieselgel/Celite beschickte Fritte filtriert, die Salze noch mit 100 mL einer CH2Cl2/Hex- Lsg. (2 : 1) nachgewaschen und einrotiert.The solution is allowed to thaw overnight, the precipitated salts are filtered through a frit charged with silica gel / Celite, the salts are washed with 100 ml of a CH 2 Cl 2 / hex solution (2: 1) and evaporated.

Nach chromatographischer Reinigung über eine 5 : 1-Hex/EE-Kieselgelsäule wurden 12.64 g (94.2%) nur sehr leicht verunreinigten Produktes erhalten.
After chromatographic purification on a 5: 1 hex / EA silica gel column, 12.64 g (94.2%) of only very slightly contaminated product were obtained.

Rf-Wert (Hex/EE= 3 : 1) ≈ 0.56
F II (rotviolett);
F III (grau)
1H-NMR (250 MHz, CDCl3) von R2-PMB: δ in ppm =
1.16 (d, J = 7.1 Hz, 3H, 2-CH3); 2.77 (tq, J = 7.1, 7.1 Hz, 1H, 2-H); 3.45 (dd, J = 9.2, 5.9 Hz, 1H, 3-H,); 3.63 (dd, J = 9.2, 7.3 Hz, 1H, 3-Hb); 3.69 (s, 1H, -CO2CH3); 3.80 (s, 3H, Ar-OCH3); 4.45 (s, 2H, -CH2-Ar); 6.87 (dt, J = 8.7, 2.4 Hz, 2H, Ar-H); 7.24 (dt, J = 8.7, 2.0 Hz, 2H, Ar-H).
R f value (Hex / EE = 3: 1) ≈ 0.56
F II (red violet);
F III (gray)
1 H-NMR (250 MHz, CDCl 3 ) of R2-PMB: δ in ppm =
1.16 (d, J = 7.1 Hz, 3H, 2-CH 3); 2.77 (tq, J = 7.1, 7.1 Hz, 1H, 2-H); 3.45 (dd, J = 9.2, 5.9 Hz, 1H, 3-H,); 3.63 (dd, J = 9.2, 7.3 Hz, 1H, 3-Hb); 3.69 (s, 1H, -CO 2 CH 3); 3.80 (s, 3H, Ar-OCH 3); 4.45 (s, 2H, -CH 2 -Ar); 6.87 (dt, J = 8.7, 2.4 Hz, 2H, Ar-H); 7.24 (dt, J = 8.7, 2.0 Hz, 2H, Ar-H).

13C-NMR (62.5 MHz, CDCl3): δ in ppm =
13.9; 40.0; 51.6; 55.1; 71.5; 72.6; 113.6; 129.1; 130.1; 159.0; 175.2.
 13 C-NMR (62.5 MHz, CDCl 3 ): δ in ppm =
13.9; 40.0; 51.6; 55.1; 71.5; 72.6; 113.6; 129.1; 130.1; 159.0; 175.2.

IR(KBr-Film): ν in cm-1 =
2951 m; 2906 m; 2860 m; 2838 m; 1738 vs; 1612 s; 1586 w; 1513 vs; 1462 m; 1436 m; 1363 m; 1302 m; 1248 vs; 1200 s; 1175 s; 1090 s; 1035 s; 996 w; 828 m; 759 w.
IR (KBr film): ν in cm -1 =
2951 m; 2906 m; 2860 m; 2838 m; 1738 vs; 1612 s; 1586 w; 1513 vs; 1462 m; 1436 m; 1363 m; 1302 m; 1248 vs; 1200 s; 1175 s; 1090 s; 1035 s; 996 w; 828 m; 759 w.

MS (EI, eV, 200°C): m/e =
238 [M⁺]; 137; 121; 109; 89; 87; 78; 77; 65; 59.
MS (EI, eV, 200 ° C): m / e =
238 [M⁺]; 137; 121; 109; 89; 87; 78; 77; 65; 59.

Drehwert: [α] 20|D = + 8.4 (c = 1.49; CHCl3)
Rotation value: [α] 20 | D = + 8.4 (c = 1.49; CHCl 3 )

C13H18O4: (M = 238.38 g.mol-1) EA:
ber.: C: 65.53% H: 7.61%
gef.: C: 65.26% H: 7.48%C 13 H 18 O 4 : (M = 238.38 g.mol -1 ) EA:
calc .: C: 65.53% H: 7.61%
found: C: 65.26% H: 7.48%

Beispiel 2Example 2 Darstellung von (+)-(2R)-[3-[(4-methoxyphenyl)methoxy]-2- methyl]propanolRepresentation of (+) - (2R) - [3 - [(4-methoxyphenyl) methoxy] -2- methyl] propanol

In 1 L abs. THF werden 12.64 g (53,08 mmol) R2-PMB bei -20°C vorgelegt. Nun werden langsam 132.7 mL (159,2 mmol) einer 1.2 M DIBAH in Toluol-Lsg. über einen Tropftrichter zugegeben, 1 h bei -20°C nachgerührt, auf Raumtemperatur erwärmen gelassen und bis zum vollständigen Umsatz weitergerührt. In 1 L abs. THF 12.64 g (53.08 mmol) R2-PMB are presented at -20 ° C. Now slowly add 132.7 mL (159.2 mmol) of a 1.2 M DIBAH in toluene solution. about one Added dropping funnel, stirred at -20 ° C for 1 h, warmed to room temperature left and continue stirring until complete conversion.  

Zum Reaktionsabbruch werden 18 mL MeOH bei ca. -10°C sehr vorsichtig, langsam zugegeben. Um die Al-O-Bindung aufzubrechen werden anschließend 55 mL ges. NH4Cl-Lsg. ebenfalls sehr vorsichtig zugetropft und die Lösung unter Rühren mit dem KPG-Rührer über Nacht auftauen gelassen.To terminate the reaction, 18 mL MeOH are added very slowly at approx. -10 ° C. To break the Al-O bond, 55 mL are then sat. NH 4 Cl solution. also added very carefully and allowed to thaw the solution overnight with the KPG stirrer.

In aller Regel erhält man bei dieser Aufarbeitung sehr gut filtrierbare, kristalline Aluminiumsalze. Nach Filtration und Entfernung des Solvens am Rotationsverdampfer wurden 8.44 g Rohprodukt erhalten. Das schon recht saubere Rohprodukt wird über eine 1 : 1-Hex/EE-Kieselgelsäule chromatographiert. Es wurden schließlich 7 g Reinprodukt (91.4%) erhalten.
As a rule, this work-up gives very easily filterable, crystalline aluminum salts. After filtration and removal of the solvent on a rotary evaporator, 8.44 g of crude product were obtained. The already clean crude product is chromatographed on a 1: 1 hex / EA silica gel column. Finally 7 g of pure product (91.4%) were obtained.

Rf-Wert (Hex/EE= 3 : 1) ≈ 0.23
F II (rotviolett);
F III (grau)
R f value (Hex / EE = 3: 1) ≈ 0.23
F II (red violet);
F III (gray)

1H-NMR (250 MHz, CDCl3) von R3-PMB: δ in ppm =
0.87 (d, J = 7.0 Hz, 3H, H-4); 2.04 (mc, 1H, H-3); 2.72 (br, 1H, H-1); 3.39 (dd, J = 8.1, 8.0 Hz, 1H, H-5); 3.51 (dd, J = 4.8, 4.7 Hz, 1H, H-5); 3.58 (mc, 2H, H-2); 3.80 (s, 3H, H-9); 4.44 (s, 2H, H-6); 6.88 (d(t), J = 8.7, (2.0) Hz, 2H, H-8); 7.24 (d(t), J = 8.7, (1.9) Hz, 2H, H-7).
 1 H-NMR (250 MHz, CDCl 3 ) of R3-PMB: δ in ppm =
0.87 (d, J = 7.0 Hz, 3H, H-4); 2.04 (mc, 1H, H -3); 2.72 (br, 1H, H-1); 3.39 (dd, J = 8.1, 8.0 Hz, 1H, H-5); 3.51 (dd, J = 4.8, 4.7 Hz, 1H, H-5); 3.58 (mc, 2H, H-2); 3.80 (s, 3H, H-9); 4.44 (s, 2H, H-6); 6.88 (d (t), J = 8.7, (2.0) Hz, 2H, H-8); 7.24 (d (t), J = 8.7, (1.9) Hz, 2H, H-7).

13C-NMR (62.5 MHz, CDCl3): δ in ppm =
13.4; 35.4; 55.1; 67.5; 72.9; 74.8; 113.7; 129.1; 130.0; 159.1.
 13 C-NMR (62.5 MHz, CDCl 3 ): δ in ppm =
13.4; 35.4; 55.1; 67.5; 72.9; 74.8; 113.7; 129.1; 130.0; 159.1.

IR(KBr-Film): ν in cm-1 =
3425 br; 2957 s; 2908 s; 2872 s; 2060 w; 1884 w; 1721 w; 1613 s; 1586 m; 1513 vs; 1464 m; 1363 m; 1302 m; 1248 vs; 1174 m; 1090 s; 1036 vs; 820 s; 757 w.
IR (KBr film): ν in cm -1 =
3425 br; 2957 s; 2908 s; 2872 s; 2060 w; 1884 w; 1721 w; 1613 s; 1586 m; 1513 vs; 1464 m; 1363 m; 1302 m; 1248 vs; 1174 m; 1090 s; 1036 vs; 820 s; 757 w.

MS (EI, 70 eV, 40°C): m/e =
210 [M⁺]; 137; 121; 109; 89; 78; 77; 55; 52; 51.
MS (EI, 70 eV, 40 ° C): m / e =
210 [M⁺]; 137; 121; 109; 89; 78; 77; 55; 52; 51.

Drehwert: [α] 20|D = +16.6(c= 1.16;CHCl3)
Rotation value: [α] 20 | D = +16.6 (c = 1.16; CHCl 3 )

C12H18O3: (M = 210.14g.mol-1) EA:
ber.: C: 68.55% H: 8.64%;
gef: C: 68.27% H: 8.45%. C 12 H 18 O 3 : (M = 210.14g.mol -1 ) EA:
calc .: C: 68.55% H: 8.64%;
found: C: 68.27% H: 8.45%.

Beispiel 3Example 3 Darstellung von (+)-(2S)-[3-[(4-methoxyphenyl)methoxy]-2- methyl]propanalRepresentation of (+) - (2S) - [3 - [(4-methoxyphenyl) methoxy] -2- methyl] propanal

In einem 500 mL-Dreihalsrundkolben mit Innenthermometer werden 5.1 mL (58 mmol) Oxalylchlorid in 80 mL abs. CH2Cl2 vorgelegt und auf -78°C abgekühlt. Nun werden 9.26 (131,75 mmol) mL DMSO zugegeben und 15 min nachgerührt.5.1 mL (58 mmol) of oxalyl chloride in 80 mL abs. Are in a 500 mL three-necked round bottom flask with an internal thermometer. CH 2 Cl 2 submitted and cooled to -78 ° C. Now 9.26 (131.75 mmol) mL DMSO are added and stirring is continued for 15 min.

Zur Lösung werden 11.075 g (52,7 mmol) R3-PMB in 40 mL abs. CH2Cl2 zugegeben, 30 min nachgerührt, wobei die Temperatur auf etwa -40°C ansteigen darf Man gibt nun 46 mL Hünigbase (5 eq) hinzu, rührt 30 min nach und entfernt dann das Kühlbad.11.075 g (52.7 mmol) of R3-PMB in 40 mL abs. CH 2 Cl 2 added, stirring continued for 30 min, the temperature being allowed to rise to about -40 ° C. 46 mL of Hunig base (5 eq) are now added, stirring is continued for 30 min and then the cooling bath is removed.

Bei 0°C werden 200 mL Eiswasser zugefügt, die Phasen getrennt und die wäßrige Phase noch zweimal mit Ether extrahiert. Die vereinigten organischen Phasen werden nacheinander mit ges. NH4Cl-Lsg., H2O, ges. NaHCO3-Lsg., H2O und Brine gewaschen. Die organische Phase wird über Magnesiumsulfat getrocknet, filtriert und einrotiert. Der verbleibende Rohaldehyd 9.55 g (87.1% Ausbeute) wird aufgrund der Racemerisierungsgefahr so gleich weiter umgesetzt.
At 0 ° C, 200 mL ice water are added, the phases are separated and the aqueous phase is extracted twice with ether. The combined organic phases are successively with sat. NH 4 Cl solution, H 2 O, sat. NaHCO 3 solution, H 2 O and Brine washed. The organic phase is dried over magnesium sulfate, filtered and evaporated. The remaining crude aldehyde 9.55 g (87.1% yield) is immediately converted due to the risk of racemerization.

Rf-Wert (Hex/EE= 3 : 1) ≈ 0.41
F II(rotviolett);
F V (spontan orange)
R f value (Hex / EE = 3: 1) ≈ 0.41
F II (red violet);
FV (spontaneously orange)

1H-NMR (250 MHz, CDCl3) für R4-PMB: δ in ppm =
1.12 (d, J = 7.1 Hz, 3H, H-3); 2.65 (qddd, J = 7.0, 7.0, 5.2, 1.6 Hz, 1H, H-2); 3.60 (dd, J = 9.4, 5.3 Hz, 1H, H-4); 3.66 (dd, J = 9.4, 6.7 Hz, 1H, H-4); 3.81 (s, 3H, H-8); 4.46 (s, 2H, H-5); 6.88 (d, J = 8.7 Hz, 2H, H-6); 7,24 (d, J = 8.7 Hz, 2H, H-7); 9.71 (d, J = 1.5 Hz, 1H, H-1).
 1 H-NMR (250 MHz, CDCl 3 ) for R4-PMB: δ in ppm =
1.12 (d, J = 7.1 Hz, 3H, H-3); 2.65 (qddd, J = 7.0, 7.0, 5.2, 1.6 Hz, 1H, H-2); 3.60 (dd, J = 9.4, 5.3 Hz, 1H, H-4); 3.66 (dd, J = 9.4, 6.7 Hz, 1H, H-4); 3.81 (s, 3H, H-8); 4.46 (s, 2H, H-5); 6.88 (d, J = 8.7 Hz, 2H, H-6); 7.24 (d, J = 8.7 Hz, 2H, H-7); 9.71 (d, J = 1.5 Hz, 1H, H-1).

13C-NMR (62.5 MHz, CDCl3): δ in ppm =
10.6; 46.6; 55.1; 69.7; 72.8; 113.7; 129.1; 129.9; 159.1; 203.8.
 13 C-NMR (62.5 MHz, CDCl 3 ): δ in ppm =
10.6; 46.6; 55.1; 69.7; 72.8; 113.7; 129.1; 129.9; 159.1; 203.8.

IR(KBr-Film): ν in cm-1 =
2959 m; 2935 m; 2906 m; 2858 m; 2838 m; 2724 w; 1724 s; 1612 m; 1586 w; 1514 vs; 1463 m; 1360 w; 1302 m; 1248 vs; 1174 m; 1095 s; 1035 s; 966 w; 930 w; 820 m; 757 w.
IR (KBr film): ν in cm -1 =
2959 m; 2935 m; 2906 m; 2858 m; 2838 m; 2724 w; 1724 s; 1612 m; 1586 w; 1514 vs; 1463 m; 1360 w; 1302 m; 1248 vs; 1174 m; 1095 s; 1035 s; 966 w; 930 w; 820 m; 757 w.

MS (EI, 70 eV, 200°C): m/e =
208 [M⁺]; 152; 137; 135; 121; 109; 91; 86; 84; 78; 77; 65; 63; 51.
MS (EI, 70 eV, 200 ° C): m / e =
208 [M⁺]; 152; 137; 135; 121; 109; 91; 86; 84; 78; 77; 65; 63; 51.

C12H1603: (M= 208. 1 g.mol-1)C 12 H 16 0 3 : (M = 208.1 gmol -1 )

Beispiel 4Example 4 Darstellung von (2S, 3S, 4R)-[3-Hydroxy-1-([4-methoxyphenyl]­ methoxy)-2,4,6,6-tetramethyl]-oct-7-en-5-on und (2S, 3R, 4S)-[3-Hydroxy-1-([4-methoxyphenyl]­ methoxy)-2,4,6,6-tetramethyl]-oct-7-en-5-onPreparation of (2S, 3S, 4R) - [3-hydroxy-1 - ([4-methoxyphenyl] methoxy) -2,4,6,6-tetramethyl] oct-7-en-5-one and (2S, 3R, 4S) - [3-hydroxy-1 - ([4-methoxyphenyl] methoxy) -2,4,6,6-tetramethyl] oct-7-en-5-one

Zu 25.7 mL (182 mmol) Diisopropylamin in 250 mL abs. THF werden bei -20°C langsam 106.4 mL (169.6 mmol) einer 1.6 M nBuLi-Lsg. in Hexan zugegeben und 30 min nachgerührt. Die LDA-Lsg. wird nun auf -90°C abgekühlt, 20.84 g (165 mmol) des 4,4- Dimethyl-Hex-5-en-3-ons zugefügt und 30 min nachgerührt.To 25.7 mL (182 mmol) diisopropylamine in 250 mL abs. THF are at -20 ° C slowly 106.4 mL (169.6 mmol) of a 1.6 M nBuLi solution. added in hexane and 30 min stirred. The LDA solution. is now cooled to -90 ° C, 20.84 g (165 mmol) of the 4,4- Dimethyl-hex-5-en-3-one was added and stirring was continued for 30 min.

Bei -90°C wird der frisch dargestellten Rohaldehydes (≈109.3 mmol ex 23. 14 g R3-PMB), gelöst in etwas abs. THF, zu der Enolat-Lsg. langsam zugetropft. Nach DC- Kontrolle ist die Reaktion nach ca. 10 min bereits vollständig abgelaufen. At -90 ° C the freshly prepared crude aldehyde (≈109.3 mmol ex 23. 14 g R3-PMB), solved in a little abs. THF, to the enolate solution. slowly added dropwise. After DC The reaction is complete after about 10 minutes.  

Nun wird das Kühlbad entfernt und einige Milliliter Wasser zugefügt. Die organische Phase wird anschließend abgetrennt, über Magnesiumsulfat getrocknet und das Solvens am Rotationsverdampfer entfernt.Now the cooling bath is removed and a few milliliters of water are added. The organic phase is then separated off, dried over magnesium sulfate and the solvent is removed on a rotary evaporator.

Nach chromatographischer Reinigung über eine 5 : 1-Hex/EE-Kieselgelsäule wurden 31.8 g (86.5%) Diastereomerengemisch über die zwei Stufen (Oxidation und Aldol-Addition) erhalten. Bei kleineren Mengen kann die Diastereomerentrennung durch zweifache Chromatographie erfolgen. Bei größeren Mengen empfiehlt sich eine HPLC- Trennung bzw. eine Diastereomerentrennung auf der nachfolgenden Stufe (größerer Rf Wert-Unterschied).
After chromatographic purification on a 5: 1 hex / EA silica gel column, 31.8 g (86.5%) of diastereomer mixture were obtained via the two stages (oxidation and aldol addition). For smaller amounts, the diastereomers can be separated by double chromatography. For larger quantities, HPLC separation or diastereomer separation at the subsequent stage is recommended (larger R f value difference).

Rf-Wert von R5-1-PMB (Hex/EE= 3 : 1 ≈ 0.44 F III (blaugrau)
R f value of R5-1-PMB (Hex / EE = 3: 1 ≈ 0.44 F III (blue-gray)

1H-NMR (250 MHz, CDCl3) von R5-1-PMB: δ in ppm =
0.93 (d, J = 6.8 Hz, 3H, 2-CH3); 1.04 (d, J = 6.8 Hz, 3H, 4-CH3); 1.22 (s, 3H, 6a-CH3); 1.25 (s, 3H, 6b-CH3); 1.81 (br m, 1H, 2-H); 3.15 (qd, J = 7.0, 2.4 Hz, 1H, 4-H); 3.45 (dd, J = 9.0, 6.4 Hz, 1H, 1a-H); 3.51 (m, 1H, 1b-H); 3,52 (s, 1H, 3-OH); 3.59 (dd, J = 9.2, 4.0 Hz, 1H, 3-H); 3.80 (s, 3H, OCH3); 4.44 (dd, J = 16.4, 11.6 Hz, 2H, OCH2Ar); 5.20 (d, J = 17.2 Hz, 1H, 8a-H); 5.20 (d, J = 10.8 Hz, 1H, 8b-H); 5.88 (dd, J = 17.2, 10.6 Hz, 1H, 7-H); 6,88 (mc, 2H, CHarom); 7.25 (mc, 2H, CHarom).
 1 H-NMR (250 MHz, CDCl 3 ) of R5-1-PMB: δ in ppm =
0.93 (d, J = 6.8 Hz, 3H, 2-CH 3); 1:04 (d, J = 6.8 Hz, 3H, 4-CH 3); 1.22 (s, 3H, 6a-CH3); 1.25 (s, 3H, 6b-CH 3); 1.81 (br m, 1H, 2-H); 3.15 (qd, J = 7.0, 2.4 Hz, 1H, 4-H); 3.45 (dd, J = 9.0, 6.4 Hz, 1H, 1a-H); 3.51 (m, 1H, 1b-H); 3.52 (s, 1H, 3-OH); 3.59 (dd, J = 9.2, 4.0 Hz, 1H, 3-H); 3.80 (s, 3H, OCH 3 ); 4.44 (dd, J = 16.4, 11.6 Hz, 2H, OCH 2 Ar); 5.20 (d, J = 17.2 Hz, 1H, 8a-H); 5.20 (d, J = 10.8 Hz, 1H, 8b-H); 5.88 (dd, J = 17.2, 10.6 Hz, 1H, 7-H); 6.88 (mc, 2H, CH aroma ); 7.25 (mc, 2H, CH aroma ).

13C-NMR (62.5 MHz, CDCl3): δ in ppm =
10.7; 14.1; 23.0; 23.2; 36.1; 41.0; 51.6; 55.1; 72.4; 72.8; 73.3; 113.7; 115.1; 129.1; 130.5; 141.4; 159.0; 218.5.
 13 C-NMR (62.5 MHz, CDCl 3 ): δ in ppm =
10.7; 14.1; 23.0; 23.2; 36.1; 41.0; 51.6; 55.1; 72.4; 72.8; 73.3; 113.7; 115.1; 129.1; 130.5; 141.4; 159.0; 218.5.

IR (KBr-Film): ν in cm-1 =
3497 br; 2971 s; 2935 s; 2876 m; 1692 s; 1633 m; 1613 m; 1586 w; 1514 vs; 1463 m; 1414 w; 1378 w; 1363 w; 1302 m; 1248 vs; 1173 m; 1087 s; 1036 s; 1010 m; 992 m; 981 m; 923 w; 824 m; 756 w.
IR (KBr film): ν in cm -1 =
3497 br; 2971 s; 2935 s; 2876 m; 1692 s; 1633 m; 1613 m; 1586 w; 1514 vs; 1463 m; 1414 w; 1378 w; 1363 w; 1302 m; 1248 vs; 1173 m; 1087 s; 1036 s; 1010 m; 992 m; 981 m; 923 w; 824 m; 756 w.

MS (EI, 70 eV, 80°C): m/e =
334 [M⁺]; 316 (M-H2O); 287; 241; 227; 213; 208; 207; 197; 190; 175; 149; 137; 121; 69.
MS (EI, 70 eV, 80 ° C): m / e =
334 [M⁺]; 316 (MH 2 O); 287; 241; 227; 213; 208; 207; 197; 190; 175; 149; 137; 121; 69.

Drehwert: [α] 20|D = -14.2 (c= 0.675; CHCl3)
Rotation value: [α] 20 | D = -14.2 (c = 0.675; CHCl 3 )

C20H30O4: (M = 334.2g.mol-1) EA:
ber.: C: 71.82% H: 9.04%
gef: C: 71.82% H: 8.95% C 20 H 30 O 4 : (M = 334.2g.mol -1 ) EA:
calc .: C: 71.82% H: 9.04%
found: C: 71.82% H: 8.95%

Beispiel 5Example 5

Darstellung von [2R, 2-(2S, 4S, 5S)]-{4,4-Dimethyl-2-[2-(4-methoxy­ phenyl)-5-methyl-1,3-dioxan-4-yl]}hex-5-en-3-on und [2S, 2-(2S, 4R, 5R)]-{(4,4-Dimethyl-2-[2-(4-methoxy­ phenyl)-5-methyl-1,3-dioxan-4-yl]}hex-5-en-3-on
Preparation of [2R, 2- (2S, 4S, 5S)] - {4,4-dimethyl-2- [2- (4-methoxyphenyl) -5-methyl-1,3-dioxan-4-yl]} hex-5-en-3-one and [2S, 2- (2S, 4R, 5R)] - {(4,4-dimethyl-2- [2- (4-methoxyphenyl) -5-methyl-1, 3-dioxan-4-yl]} hex-5-en-3-one

In 250 mL abs. CH2Cl2 mit ca. 3 g zerstoßenem, aktiviertem 4A Molsieb, werden 8.43 g (25.22 mmol) R5-1-PMB bei -15°C vorgelegt.In 250 mL abs. CH 2 Cl 2 with about 3 g of crushed, activated 4A molecular sieve, 8.43 g (25.22 mmol) of R5-1-PMB are placed at -15 ° C.

Nun werden langsam 6.9 g (30,26 mmol) DDQ fest zugegeben, wobei sich die Lösung sogleich tiefblau, aufgrund der Charge-Transfer-Bildung färbt. Die Reaktionslösung wird nun langsam, über einen Zeitraum von etwa 3 h auf 0°C erwärmen gelassen.Now 6.9 g (30.26 mmol) of DDQ are slowly added, the Solution immediately turns deep blue, stains due to the charge transfer formation. The The reaction solution is then slowly warmed to 0 ° C. over a period of about 3 h calmly.

Zur Aufarbeitung wird die Reaktionslösung über eine mit Kieselgel beschickte lange G3-Fritte filtriert und die Fritte noch mit CH2Cl2 und 4 : 1-Hex/EE nachgewaschen. Nach Entfernung des Solvens am Rotationsverdampfer und chromatographischer Reinigung über eine 5 : 1-Hex/EE-Kieselgelsäule erhielt man 7.2 g (86%) sehr sauberen Produktes (R6-1-PMP) und noch 0.69 g Edukt-Produkt-Mischfraktion.For working up, the reaction solution is filtered through a long G3 frit charged with silica gel and the frit is washed with CH 2 Cl 2 and 4: 1-Hex / EE. After removal of the solvent on a rotary evaporator and chromatographic purification on a 5: 1 hex / EA silica gel column, 7.2 g (86%) of very clean product (R6-1-PMP) and 0.69 g of educt-product mixed fraction were obtained.

(In dieser Reaktion verwendetes Gemisch der Diastereoisomeren von R5-PMB lassen sich nach erfolgter Acetalisierung relativ leicht, chromatographisch trennen):
(Mixture of the diastereoisomers of R5-PMB used in this reaction can be separated relatively easily, chromatographically, after acetalization has taken place):

Rf-Wert von R6-1-PMB (Hex/EE= 3 : 1) ≈ 0.53 F III (blaugrau)
R f value of R6-1-PMB (Hex / EE = 3: 1) ≈ 0.53 F III (blue-gray)

1H-NMR (250 MHz, CDCl3) von R6-1-PMP: δ in ppm =
0.75 (d, J = 6.9 Hz, 3H, 5'-CH3); 1.15 (d, J = 6.9 Hz, 3H, 1-H); 1.27 (d, J = 3.6 Hz, 6H, 4a u. 4b-CH3); 1.96 (mc, 1H, 5'-H); 3.27 (qd, J = 6.9, 4.1 Hz, 1H, 2- H); 3.48 (t(dd),J = 11.3 Hz, 1H, 6a'-H); 3.76 (dd,J = 9.9,4.1 Hz, 1H, 4'-H); 3,79 (s, 1H, OCH3); 4.06 (dd, J = 11.3+4.7 Hz, 1H, 6b'-H); 5.17 (d, J = 10.7 Hz, 1H, 6a-H); 5.21 (d, J = 17.6 Hz, 1H, 6b-H); 5.38 (s, 1H, -O2CHAr); 6.01 (dd, J = 17.6, 10.7 Hz, 1H, 5-H); 6.86 (mc, 2H, CHarom); 7.39 (mc, 2H, CHarom).
 1 H-NMR (250 MHz, CDCl 3 ) of R6-1-PMP: δ in ppm =
0.75 (d, J = 6.9 Hz, 3H, 5'-CH 3 ); 1.15 (d, J = 6.9 Hz, 3H, 1-H); 1.27 (d, J = 3.6 Hz, 6H, 4a and 4b-CH 3 ); 1.96 (mc, 1H, 5'-H); 3.27 (qd, J = 6.9, 4.1 Hz, 1H, 2H); 3.48 (t (dd), J = 11.3 Hz, 1H, 6a'-H); 3.76 (dd, J = 9.9.4.1 Hz, 1H, 4'-H); 3.79 (s, 1H, OCH 3 ); 4.06 (dd, J = 11.3 + 4.7 Hz, 1H, 6b'-H); 5.17 (d, J = 10.7 Hz, 1H, 6a-H); 5.21 (d, J = 17.6 Hz, 1H, 6b-H); 5:38 (s, 1H, CHAr 2 -O); 6.01 (dd, J = 17.6, 10.7 Hz, 1H, 5-H); 6.86 (mc, 2H, CH aroma ); 7.39 (mc, 2H, CH aroma ).

13C-NMR (62.5 MHz, CDCl3): δ in ppm =
12.6; 12.8; 24.0; 24.3; 32.1; 43.4; 51.3; 55.2; 72.8; 82.3; 100.6; 113.4; 114.2; 127.1; 131.0; 142.6; 159.7; 213.1.
 13 C-NMR (62.5 MHz, CDCl 3 ): δ in ppm =
12.6; 12.8; 24.0; 24.3; 32.1; 43.4; 51.3; 55.2; 72.8; 82.3; 100.6; 113.4; 114.2; 127.1; 131.0; 142.6; 159.7; 213.1.

IR(KBr-Film): ν in cm-1 =
3082.9 w; 2968.4 s; 2936.3 s; 2875.5 m; 2837.2 m; 1707.0 vs; 1633.1 m; 1615.4 s; 1588.0 w; 1517.9 vs; 1461.6 s; 1416.1 w; 1391.2 s; 1370.7 m; 1337.8 w; 1302.3 m; 1248.9 vs; 1171.6 m; 1115.5 s; 1077.9 s; 1035.6 s; 1012.9 s; 994.0 m; 980.2 m; 921.7 m; 828.6 s; 784.1 w; 665.2 w; 618.1 w.
IR (KBr film): ν in cm -1 =
3082.9 w; 2968.4 s; 2936.3 s; 2875.5 m; 2837.2 m; 1707.0 vs; 1633.1 m; 1615.4 s; 1588.0 w; 1517.9 vs; 1461.6 s; 1416.1 w; 1391.2 s; 1370.7 m; 1337.8 w; 1302.3 m; 1248.9 vs; 1171.6 m; 1115.5 s; 1077.9 s; 1035.6 s; 1012.9 s; 994.0 m; 980.2 m; 921.7 m; 828.6 s; 784.1 w; 665.2 w; 618.1 w.

MS (EI, 70 eV,°C): m/e =
277; 263; 207; 196; 152; 137; 135; 127; 121; 83; 71; 69.
MS (EI, 70 eV, ° C): m / e =
277; 263; 207; 196; 152; 137; 135; 127; 121; 83; 71; 69.

Drehwert: [α] 20|D = +15.5 (c= 1.34; CHCl3)
Rotation value: [α] 20 | D = +15.5 (c = 1.34; CHCl 3 )

C20H28O4: (M= 332.2 g.mol-1) EA:
ber.: C: 72.26% H: 8.49%
gef.: C: 72.02% H: 8.41% C 20 H 28 O 4 : (M = 332.2 g.mol -1 ) EA:
calc .: C: 72.26% H: 8.49%
found: C: 72.02% H: 8.41%

Beispiel 6Example 6 Darstellung von [4R, 2(2S, 4S, 5S)]-{2,2-Dimethyl-4-[2-(4-methoxy­ phenyl)-5-methyl-1,3-dioxan-4-yl]-3-oxo}pentanalPreparation of [4R, 2 (2S, 4S, 5S)] - {2,2-dimethyl-4- [2- (4-methoxy phenyl) -5-methyl-1,3-dioxan-4-yl] -3-oxo} pentanal

In 100 mL abs. CH2Cl2/MeOH (1 : 1) werden 1 g (3 mmol) R6-1-PMP bei -78°C vorgelegt. Die Lösung wird nun bei -78°C bis zur leichten Blaufärbung ozonisiert. Nun wird der Ozongenerator abgeschaltet, noch Sauerstoff bis zur Entfarbung durchgeleitet und dann zum Aufbrechen des Sekundärozonides DMS im Überschuß zugegeben.In 100 mL abs. CH 2 Cl 2 / MeOH (1: 1), 1 g (3 mmol) of R6-1-PMP are placed at -78 ° C. The solution is now ozonized at -78 ° C until a light blue color. Now the ozone generator is switched off, oxygen is passed through until it decolorises and then an excess is added to break up the secondary ozonide DMS.

Die Reaktionslösung wird aufgrund der Explosionsgefahr sehr langsam erwärmen gelassen (< 4 h), bei -10°C zunächst das überschüssige DMS und etwas Solvens im Wasserstrahlvakuum entfernt. Der Rest des Solvens kann nun am Rotationsverdampfer ohne übermäßige Geruchsbelästigung entfernt werden.The reaction solution will heat up very slowly due to the risk of explosion left (<4 h), at -10 ° C the excess DMS and some solvent in the Water jet vacuum removed. The rest of the solvent can now be used on a rotary evaporator can be removed without excessive odor nuisance.

Zur Reinigung des Rohaldehydes muß dieser schnell über eine 3 : 1-Hex/EE- Kieselgelsäule chromatographiert werden, da der Aldehyd auf der Säule zur Retroaldol- Zersetzung neigt.To clean the crude aldehyde, it must be quickly removed using a 3: 1 hex / EE Silica gel column, since the aldehyde on the column forms a retroaldol Decomposition tends.

Die Ausbeuten liegen aus diesem Grunde meist nur bei 80%, wobei im vorliegenden Fall mit 930 mg (92.4%) die beste bisher erzielte Ausbeute erhalten wurde.
For this reason, the yields are usually only 80%, and in the present case the best yield to date has been obtained with 930 mg (92.4%).

Rf-Wert (Hex/EE= 3 : 1) ≈ 0.37
F III (graubraun);
F V (spontan orange)
R f value (Hex / EE = 3: 1) ≈ 0.37
F III (gray-brown);
FV (spontaneously orange)

1H-NMR (250 MHz, CDCl3) von R7-1-PMP: δ in ppm =
0.79 (d, J = 6.7 Hz, 3H, 5'-CH3); 1.16 (d, J = 6.9 Hz, 3H, 5-H); 1.32 (s, 3H, 2a- CH3); 1.42 (s, 3H, 2b-CH3); 2.01 (mc, 1H, 5'-H); 3.17 (qd, J = 6.9, 3.7 Hz, 1H, 4-H); 3.50 (t(dd), J = 11.2 Hz, 1H, 6a'-H); 3.78 (s, 3H, OCH3); 3,79 (v, 1H, 4'- H); 4.06 (dd, J = 11.3, 4.8 Hz, 1H, 6b'-H); 5.26 (s, 1H, -O2CHAr); 6.85 (mc, 2H, CHarom); 7.33 (mc, 2H, CHarom; 9.36 (s, 1H, -CHO).
 1 H-NMR (250 MHz, CDCl 3 ) of R7-1-PMP: δ in ppm =
0.79 (d, J = 6.7 Hz, 3H, 5'-CH 3 ); 1.16 (d, J = 6.9 Hz, 3H, 5-H); 1:32 (s, 3H, 2a-CH 3); 1:42 (s, 3H, 2b-CH 3); 2.01 (mc, 1H, 5'-H); 3.17 (qd, J = 6.9, 3.7 Hz, 1H, 4-H); 3.50 (t (dd), J = 11.2 Hz, 1H, 6a'-H); 3.78 (s, 3H, OCH 3 ); 3.79 (v, 1H, 4'-H); 4.06 (dd, J = 11.3, 4.8 Hz, 1H, 6b'-H); 5.26 (s, 1H, CHAr 2 -O); 6.85 (mc, 2H, CH aroma ); 7.33 (mc, 2H, CH aroma ; 9.36 (s, 1H, -CHO).

13C-NMR (62.5 MHz, CDCl3): δ in ppm =
10.3; 12.2; 19.3; 20.4; 31.2; 45.0; 55.3; 61.2; 72.7; 81.2; 100.8; 113.5; 127.2; 132.0; 159.9; 200.2; 208.3.
 13 C-NMR (62.5 MHz, CDCl 3 ): δ in ppm =
10.3; 12.2; 19.3; 20.4; 31.2; 45.0; 55.3; 61.2; 72.7; 81.2; 100.8; 113.5; 127.2; 132.0; 159.9; 200.2; 208.3.

IR(KBrFilm): ν in cm-1 =
2967 m; 2938 m; 2876 w; 2838 m; 2720 w; 1734 m; 1698 vs; 1615 m; 1588 w; 1518 s; 1462 m; 1393 m; 1369 m; 1303 m; 1250 vs; 1172 m; 1127 m; 1111 m; 1076 s; 1032 s; 994 m; 973 m; 908 w; 830 m; 739 w; 707 s; 667 w.
IR (KBrFilm): ν in cm -1 =
2967 m; 2938 m; 2876 w; 2838 m; 2720 w; 1734 m; 1698 vs; 1615 m; 1588 w; 1518 s; 1462 m; 1393 m; 1369 m; 1303 m; 1250 vs; 1172 m; 1127 m; 1111 m; 1076 s; 1032 s; 994 m; 973 m; 908 w; 830 m; 739 w; 707 s; 667 w.

MS (EI, 70 eV, 140°C): m/e =
334[M⁺]; 333(M-H); 306(M-CO); 278; 263; 236; 207; 182; 181; 152; 137; 136; 121; 109; 99; 77; 71; 69; 55.
MS (EI, 70 eV, 140 ° C): m / e =
334 [M⁺]; 333 (MH); 306 (M-CO); 278; 263; 236; 207; 182; 181; 152; 137; 136; 121; 109; 99; 77; 71; 69; 55.

C19H26O5: (M= 334.2 g.mol-1)C 19 H 26 O 5 : (M = 334.2 g.mol -1 )

Beispiel 7Example 7 Darstellung von [2R, 2(2S, 4S, 5S), 5S]-{5-Hydroxy-4,4-dimethyl-2-[2- (4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]}oct-7-en-3-on und [2R, 2(2S, 4S, 5S), 5R]-{(5-Hydroxy-4,4-dimethyl-2-[2- (4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]}oct-7-en-3-onPreparation of [2R, 2 (2S, 4S, 5S), 5S] - {5-hydroxy-4,4-dimethyl-2- [2- (4-methoxyphenyl) -5-methyl-1,3-dioxan-4-yl]} oct-7-en-3-one and [2R, 2 (2S, 4S, 5S), 5R] - {(5-hydroxy-4,4-dimethyl-2- [2- (4-methoxyphenyl) -5-methyl-1,3-dioxan-4-yl]} oct-7-en-3-one

In 10 mL abs. Diethylether werden 494 mg (1.54 mmol) DIPCl bei -78°C vorgelegt und mit 1.54 mL einer 1 M Allylmagnesiumbromid-Lsg. versetzt, 30 min bei -78°C nachgerührt und dann langsam auf Raumtemperatur erwärmen gelassen, wobei MgBrCl ausfällt.In 10 mL abs. Diethyl ether and 494 mg (1.54 mmol) of DIPCl are introduced at -78 ° C with 1.54 mL of a 1 M allyl magnesium bromide solution. mixed, 30 min at -78 ° C stirred and then slowly allowed to warm to room temperature, MgBrCl fails.

Nach Abkühlung des Allylboran-Reagenzes auf -78°C werden 490 mg (1.465 mmol) R7-1-PMP, gelöst in etwas Ether, per Injektionsapparat über einen Zeitraum von 3 h langsam zugetropft. Anschließend wird auf Raumtemperatur erwärmen gelassen, die ausgefallenen Salze abfiltriert und die Lösung am Rotationsverdampfer eingeengt.After cooling the allylborane reagent to -78 ° C, 490 mg (1.465 mmol) R7-1-PMP, dissolved in some ether, by injection over a period of Slowly added dropwise for 3 h. The mixture is then allowed to warm to room temperature precipitated salts are filtered off and the solution is concentrated on a rotary evaporator.

Der Rückstand wird in etwas Ether aufgenommen mit 1.46 mL 3 N NaOH und 0.6 mL 30%ige Wasserstoffperoxid-Lsg. versetzt und bei RT über Nacht kräftig gerührt.The residue is taken up in a little ether with 1.46 mL 3 N NaOH and 0.6 mL 30% hydrogen peroxide solution. added and stirred vigorously at RT overnight.

Bei vollständigem Umsatz (DC-Kontrolle) wird von nachgefallenen Salzen abfiltriert, mit Ether nachgewaschen, die Phasen getrennt, die organische Phase mit ges. NH4Cl-Lsg., Wasser und Brine ausgeschüttelt, über Magnesiumsulfat getrocknet, filtriert und einrotiert.When the conversion is complete (TLC control), the salts which have precipitated are filtered off, washed with ether, the phases are separated and the organic phase is saturated. NH 4 Cl solution, water and brine shaken out, dried over magnesium sulfate, filtered and evaporated.

Das Rohprodukt wird anschließend über eine 3 : 1-Hex/EE-Kieselgelsäule chromatographiert. Man erhielt 408 mg (74%) Diastereomerengemisch (81 : 19) R8-1- PMP, welches auf der präparativen HPLC-Anlage getrennt wurde.
The crude product is then chromatographed on a 3: 1 hex / EA silica gel column. This gave 408 mg (74%) of diastereomer mixture (81:19) of R8-1-PMP, which was separated on the preparative HPLC system.

1H-NMR (250 MHz, CDCl3) von R8-1-P1: δ in ppm =
0.87 (d, J = 6.7 Hz, 3H, 5'-CH3); 1.17-1.25 (v, 9H, 1-H, 4a u. 4b-CH3); 2.04 (m, 2H, 5'-H u. 6a-H); 2.22 (m, 1H, 6b-H); 2.76 (d, J = 5.4 Hz, 1H, 5-OH); 3.40 (qd, J = 7.1,3.0Hz, 1H, 2-H); 3.49 (t, J = 11.2Hz, 1H, 6a'-H); 3.73 (dd, J = 10.0, 3.0 Hz, 1H, 4'-H); 3,79 (s, 1H, OCH3); 3.81 (v, 1H, 5-H); 4.07 (dd, J = 11.3, 4.8 Hz, 1H, 6b'-H); 5.02 (m, 1H, 8a-H); 5.08 (m, 1H, 8b-H); 5.41 (s, 1H, - O2CHAr); 5.80 (m, 1H, 7-H); 6.87 (mc, 2H, CHarom); 7.37 (mc, 2H, CHarom).
 1 H-NMR (250 MHz, CDCl 3 ) of R8-1-P1: δ in ppm =
0.87 (d, J = 6.7 Hz, 3H, 5'-CH 3 ); 1.17-1.25 (v, 9H, 1-H, 4a and 4b-CH 3 ); 2.04 (m, 2H, 5'-H and 6a-H); 2.22 (m, 1H, 6b-H); 2.76 (d, J = 5.4 Hz, 1H, 5-OH); 3.40 (qd, J = 7.1.3.0Hz, 1H, 2-H); 3.49 (t, J = 11.2Hz, 1H, 6a'-H); 3.73 (dd, J = 10.0, 3.0 Hz, 1H, 4'-H); 3.79 (s, 1H, OCH 3 ); 3.81 (v, 1H, 5-H); 4.07 (dd, J = 11.3, 4.8 Hz, 1H, 6b'-H); 5.02 (m, 1H, 8a-H); 5.08 (m, 1H, 8b-H); 5.41 (s, 1H, - O 2 CHAr); 5.80 (m, 1H, 7-H); 6.87 (mc, 2H, CH aroma ); 7.37 (mc, 2H, CH aroma ).

13C-NMR (62.5 MHz, CDCl3): δ in ppm =
12.7; 13.6; 19.0; 22.0; 31.7; 35.9; 43.6; 52.5; 55.1; 72.9; 75.4; 83.6; 100.8; 113.4; 117.0; 127.1; 130.5; 135.8; 159.7; 216.8.
 13 C-NMR (62.5 MHz, CDCl 3 ): δ in ppm =
12.7; 13.6; 19.0; 22.0; 31.7; 35.9; 43.6; 52.5; 55.1; 72.9; 75.4; 83.6; 100.8; 113.4; 117.0; 127.1; 130.5; 135.8; 159.7; 216.8.

IR(KBr-Film): ν in cm-1 =
3484 br; 3074 w; 2960 s; 2838 m; 1703 s; 1640 w; 1615 m; 1588 w; 1518 vs; 1463 m; 1391 s; 1369 m; 1303 m; 1250 vs; 1172 m; 1126 m; 1110 m; 1077 s; 1034 vs; 992 s; 914 w; 874 w; 829 m; 784 w.
IR (KBr film): ν in cm -1 =
3484 br; 3074 w; 2960 s; 2838 m; 1703 s; 1640 w; 1615 m; 1588 w; 1518 vs; 1463 m; 1391 s; 1369 m; 1303 m; 1250 vs; 1172 m; 1126 m; 1110 m; 1077 s; 1034 vs; 992 s; 914 w; 874 w; 829 m; 784 w.

MS (EI, 70 eV,°C): m/e =
376 [M⁺]; 375; 335; 306; 305; 279; 277; 244; 243; 207; 170; 165; 137; 136; 135; 123; 91; 71.
MS (EI, 70 eV, ° C): m / e =
376 [M⁺]; 375; 335; 306; 305; 279; 277; 244; 243; 207; 170; 165; 137; 136; 135; 123; 91; 71.

C22H32O5: (M= 376.25 g.mol-1) EA:
ber.: C: 70.185% H: 8.57%
gef.: C: 69.99% H: 8.52%C 22 H 32 O 5 : (M = 376.25 g.mol -1 ) EA:
calc .: C: 70.185% H: 8.57%
found: C: 69.99% H: 8.52%

Beispiel 8Example 8 Darstellung von [2R, 2(2S, 4S, 5S), 5S]-4,4-Dimethyl-5-[[(1,1-dimethyl­ ethyl)dimethylsilyl]oxy]-2-[2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4- yl]oct-7-en-3-onPreparation of [2R, 2 (2S, 4S, 5S), 5S] -4,4-dimethyl-5 - [[(1,1-dimethyl ethyl) dimethylsilyl] oxy] -2- [2- (4-methoxyphenyl) -5-methyl-1,3-dioxane-4- yl] oct-7-en-3-one

Bei -20°C werden in 100 mL abs. CH2Cl2 1.94 g (5.151 mmol) R8-1-P1 vorgelegt, mit 2.4 mL 2,6-Lutidin (4 eq) und 2.4 mL tert.-Butyldimethylsily-O-Triflat (2 eq) versetzt und 2-3h gerührt.At -20 ° C in 100 mL abs. CH 2 Cl 2 1.94 g (5,151 mmol) of R8-1-P1, 2.4 mL of 2,6-lutidine (4 eq) and 2.4 mL of tert-butyldimethylsily-O-triflate (2 eq) were added and the mixture was stirred for 2-3 hours .

Zur Aufarbeitung wird mit etwas ges. NH4Cl-Lsg. und Eiswasser die Reaktion abgebrochen, die Phasen getrennt, die organische noch mit ges. NH4Cl-Lsg., Wasser und Brine ausgeschüttelt, die organische Phase über Magnesiumsulfat getrocknet, filtriert und einrotiert.To work it up with something. NH 4 Cl solution. and ice water the reaction stopped, the phases separated, the organic still with sat. NH 4 Cl solution, water and brine shaken out, the organic phase dried over magnesium sulfate, filtered and evaporated.

Nach chromatographischer Reinigung über eine 10 : 1-Hex/EE-Kieselgelsäule erhielt man in praktisch quantitativer Ausbeute (3 99%) R8-1-S1.
After chromatographic purification on a 10: 1 hex / EA silica gel column, R8-1-S1 was obtained in practically quantitative yield ( 3 99%).

1H-NMR (250 MHz, CDCl3) von R8-1-S1: δ in ppm =
0.02 (s, 3H, Si-CH3); 0.05 (s, 3H, Si-CH3); 0.82 (d, J = 6.6 Hz, 3H, 5'-CH3); 0.88 (s, 9H, -C(CH3)3); 1.14 (s, 3H, 4a- CH3); 1.15 (d, J = 6.3 Hz, 3H, 1-H); 1.21 (s, 3H, 4b- CH3); 2.06 (m, 1H, 5'-H); 2.14 (mc, 2H, 6a u. 6b-H); 3.26 (qd, J = 6.9, 2.8 Hz, 1H, 2-H); 3.49 (t, J = 7.1 Hz, 1H, 6a'-H); 3.77 (s, 3H, OCH3); 3.77 (dd,J= 10.2, 2.8 Hz, 1H, 4'-H); 4.09 (dd, J = 11.3, 4.7Hz, 1H, 5-H); 4.14 (dd, J = 6.1, 4.4Hz, 1H, 6b'-H); 4.91 (m, 1H, 8a-H); 4.97 (m, 1H, 8b-H); 5.38 (s, 1H, O2CHAr); 5.81 (m' 1H, 7-H); 6.84 (mc, 2H, CHarom); 7.35 (mc, 2H, CHarom).
 1 H-NMR (250 MHz, CDCl 3 ) of R8-1-S1: δ in ppm =
0:02 (s, 3H, Si-CH 3); 0.05 (s, 3H, Si-CH 3); 0.82 (d, J = 6.6 Hz, 3H, 5'-CH 3 ); 0.88 (s, 9H, -C (CH 3) 3); 1.14 (s, 3H, 4a-CH 3); 1.15 (d, J = 6.3 Hz, 3H, 1-H); 1.21 (s, 3H, 4b- CH 3); 2.06 (m, 1H, 5'-H); 2.14 (mc, 2H, 6a and 6b-H); 3.26 (qd, J = 6.9, 2.8 Hz, 1H, 2-H); 3.49 (t, J = 7.1 Hz, 1H, 6a'-H); 3.77 (s, 3H, OCH 3 ); 3.77 (dd, J = 10.2, 2.8 Hz, 1H, 4'-H); 4.09 (dd, J = 11.3, 4.7 Hz, 1H, 5-H); 4.14 (dd, J = 6.1, 4.4Hz, 1H, 6b'-H); 4.91 (m, 1H, 8a-H); 4.97 (m, 1H, 8b-H); 5:38 (s, 1H, O 2 Ar); 5.81 (m '1H, 7-H); 6.84 (mc, 2H, CH aroma ); 7.35 (mc, 2H, CH aroma ).

13C-NMR (100 MHz, CDCl3): δ in ppm =
11.4; 12.5; 18.2; 19.3; 23.4; 26.0; 31.2; 39.1; 42.9; 54.0; 55.2; 72.9; 81.9; 100.6; 113.4; 116.2; 127.2; 130.9; 136.6; 159.7; 214.6. 13 C-NMR (100 MHz, CDCl 3 ): δ in ppm =
11.4; 12.5; 18.2; 19.3; 23.4; 26.0; 31.2; 39.1; 42.9; 54.0; 55.2; 72.9; 81.9; 100.6; 113.4; 116.2; 127.2; 130.9; 136.6; 159.7; 214.6.

Beispiel 9Example 9 Darstellung von [6R, 2(2S, 4S, 5S), 3S]-{4,4-Dimethyl-3-[[(1,1-dimethyl­ ethyl)dimethylsilyl]oxy]-6-[2-(4-methoxyphenyl)-5- methyl-1,3-dioxan-4-yl]-5-oxo}heptanalPreparation of [6R, 2 (2S, 4S, 5S), 3S] - {4,4-dimethyl-3 - [[(1,1-dimethyl ethyl) dimethylsilyl] oxy] -6- [2- (4-methoxyphenyl) -5- methyl-1,3-dioxan-4-yl] -5-oxo} heptanal

In 60 mL CH2Cl2/MeOH (20 : 1) werden 300 mg (0.61 mmol) R8-1-S1 bei -78 °C vorgelegt. Die Lösung wird bei -78°C bis zur leichten Blaufärbung ozonisiert, anschließend wird noch Sauerstoff durch die Lösung geleitet, um überschüssiges Ozon zu entfernen.300 mg (0.61 mmol) of R8-1-S1 at -78 ° C are placed in 60 mL CH 2 Cl 2 / MeOH (20: 1). The solution is ozonized at -78 ° C until it turns slightly blue, after which oxygen is passed through the solution to remove excess ozone.

Noch bei -78°C wird eine kaltgesättigte Triphenylphosphinlösung in CH2Cl2 im Überschuß zugegeben und die Lösung langsam auf Raumtemperatur erwärmen gelassen. Die Lösung wird am Rotationsverdampfer eingeengt und über eine 5 : 1 -Hex/EE- Kieselgelgelsäule chromatographiert. Es wurden 302 mg (99.7%) R9-1-S1 erhalten.
Even at -78 ° C, a cold saturated triphenylphosphine solution in CH 2 Cl 2 is added in excess and the solution is allowed to warm slowly to room temperature. The solution is concentrated on a rotary evaporator and chromatographed on a 5: 1 hex / EA silica gel column. 302 mg (99.7%) of R9-1-S1 were obtained.

1H-NMR(250MHz, CDCl3)von R9-1-S1: δ in ppm =
0.02 (s, 3H, Si-CH3); 0.06 (s, 3H, Si-CH3); 0.82 (d, J = 6.6 Hz, 3H, 5'-CH3); 0.85 (s, 9H, -C(CH3)3); 1.13 (d, J = 6.9 Hz, 3H, 6-CH3); 1.14 (s, 3H, 4a-CH3); 1.19 (s, 3H, 4b-CH3); 2.02 (mc, 1H, 5'-H); 2.38 (ddd, J = 16.8, 5.5, 3.0 Hz, 1H, 2a-H); 2.48 (ddd, J = 16.8, 4.7, 1.7 Hz, 1H, 2b-H); 3.27 (qd, J = 6.9, 3.0 Hz, 1H, 5-H); 3.49 (t, J = 11.3 Hz, 1H, 6a'-H); 3.75 (dd, J = 9.6, 3.0 Hz, 1H, 4'- H); 3.76 (s, 3H, OCH3); 4.07 (dd, J = 11.6, 5.0 Hz, 1H, 6b'-H); 4.65 (t, J = 5.5 Hz, 1H, 3-H); 5.39 (s, 1H, -O2CHAr); 6.83 (mc, 2H, CHarom); 7.33 (mc, 2H, CHarom); 9.71 (dd, J = 3.0 Hz, 1H, CHO).
 1 H-NMR (250 MHz, CDCl 3 ) of R9-1-S1: δ in ppm =
0:02 (s, 3H, Si-CH 3); 0:06 (s, 3H, Si-CH 3); 0.82 (d, J = 6.6 Hz, 3H, 5'-CH 3 ); 0.85 (s, 9H, -C (CH 3) 3); 1.13 (d, J = 6.9 Hz, 3H, 6-CH 3); 1.14 (s, 3H, 4-CH 3); 1.19 (s, 3H, 4b-CH 3); 2.02 (mc, 1H, 5'-H); 2.38 (ddd, J = 16.8, 5.5, 3.0 Hz, 1H, 2a-H); 2.48 (ddd, J = 16.8, 4.7, 1.7 Hz, 1H, 2b-H); 3.27 (qd, J = 6.9, 3.0 Hz, 1H, 5-H); 3.49 (t, J = 11.3 Hz, 1H, 6a'-H); 3.75 (dd, J = 9.6, 3.0 Hz, 1H, 4'-H); 3.76 (s, 3H, OCH 3 ); 4.07 (dd, J = 11.6, 5.0 Hz, 1H, 6b'-H); 4.65 (t, J = 5.5 Hz, 1H, 3-H); 5:39 (s, 1H, CHAr 2 -O); 6.83 (mc, 2H, CH aroma ); 7.33 (mc, 2H, CH aroma ); 9.71 (dd, J = 3.0 Hz, 1H, CHO).

13C-NMR( MHz, CDCl3): δ in ppm =
11.4; 12.4; 18.0; 18.9; 23.1; 25.8; 31.1; 42.9; 48.8; 53.5; 55.1; 71.0; 72.7; 81.8; 100.6; 113.3; 127.1; 130.7; 159.6; 201.3; 214.3.
 13 C-NMR (MHz, CDCl 3 ): δ in ppm =
11.4; 12.4; 18.0; 18.9; 23.1; 25.8; 31.1; 42.9; 48.8; 53.5; 55.1; 71.0; 72.7; 81.8; 100.6; 113.3; 127.1; 130.7; 159.6; 201.3; 214.3.

IR(KBr-Film): ν in cm-1 =
2957 s; 2934 s; 2856 s; 2723 w; 2253 w; 1726 vs; 1702 s; 1615 m; 1588 w; 1518 s; 1463 s; 1390 s; 1361 m; 1303 m; 1251 vs; 1172 m; 1159 w; 1125 m; 1099 s; 1079 s; 1035 s; 1005 s; 980 m; 938 w; 912 m; 836 vs; 777 s; 673 w; 648 w.
IR (KBr film): ν in cm -1 =
2957 s; 2934 s; 2856 s; 2723 w; 2253 w; 1726 vs; 1702 s; 1615 m; 1588 w; 1518 s; 1463 s; 1390 s; 1361 m; 1303 m; 1251 vs; 1172 m; 1159 w; 1125 m; 1099 s; 1079 s; 1035 s; 1005 s; 980 m; 938 w; 912 m; 836 vs; 777 s; 673 w; 648 w.

MS (EI, 70 eV, 240°C): m/e =
493[M⁺]; 435; 277; 263; 207; 171; 137; 129; 121; 83; 75; 73.
MS (EI, 70 eV, 240 ° C): m / e =
493 [M⁺]; 435; 277; 263; 207; 171; 137; 129; 121; 83; 75; 73.

Drehwert: [α] 20|D = -11.3 (c= 0.78; CHCl3)
Rotation value: [α] 20 | D = -11.3 (c = 0.78; CHCl 3 )

C27H44O6Si: (M= 492.7 g.mol-1) EA:
ber.: C: 65.82% H: 9.00%
gef.: C: 66.05% H: 9.17%
C 27 H 44 O 6 Si: (M = 492.7 g.mol -1 ) EA:
calc .: C: 65.82% H: 9.00%
found: C: 66.05% H: 9.17%

IR(KBr-Film): ν in cm-1 =
3075 w; 2956 vs; 2934 vs; 2856 s; 1703 s; 1640 w; 1616 m; 1588 w; 1518 s; 1471 m; 1462 s; 1389 s; 1360 m; 1302 m; 1251 vs; 1172 m; 1126 s; 1078 s; 1036 vs; 1004 s; 980 m; 938 w; 911 w; 836 vs; 810 m; 776 w; 671 w.
IR (KBr film): ν in cm -1 =
3075 w; 2956 vs; 2934 vs; 2856 s; 1703 s; 1640 w; 1616 m; 1588 w; 1518 s; 1471 m; 1462 s; 1389 s; 1360 m; 1302 m; 1251 vs; 1172 m; 1126 s; 1078 s; 1036 vs; 1004 s; 980 m; 938 w; 911 w; 836 vs; 810 m; 776 w; 671 w.

MS (EI, 70 eV, 240°C): m/e =
491[M⁺]; 433; 363; 278; 263; 252; 227; 207; 199; 185; 157; 137; 135; 121; 91; 75; 73.
MS (EI, 70 eV, 240 ° C): m / e =
491 [M⁺]; 433; 363; 278; 263; 252; 227; 207; 199; 185; 157; 137; 135; 121; 91; 75; 73.

Drehwert: [α]20 D= -4.1 (c= 0.615; CHCl3)
Rotation value: [α] 20 D = -4.1 (c = 0.615; CHCl 3 )

C28H46O5Si: (M= 490.7 g.mol-1) EA:
ber.: C: 68.53% H: 9.48%
gef.: C: 68.29% H: 9.34%C 28 H 46 O 5 Si: (M = 490.7 g.mol -1 ) EA:
calc .: C: 68.53% H: 9.48%
found: C: 68.29% H: 9.34%

Beispiel 10Example 10 Darstellung von [6R, 2(2S, 4S, 3S), 5S]-{4,4-Dimethyl-3-[[(1,1-dimethyl­ ethyl)dimethylsilyl]oxy]-6-[2-(4-methoxyphenyl)-5- methyl-1,3-dioxan-4-yl]-5-oxo}heptansäurePreparation of [6R, 2 (2S, 4S, 3S), 5S] - {4,4-dimethyl-3 - [[(1,1-dimethyl ethyl) dimethylsilyl] oxy] -6- [2- (4-methoxyphenyl) -5- methyl-1,3-dioxan-4-yl] -5-oxo} heptanoic acid

In 22.3 mL tert.-Butanol und 5.4 mL 2,3-Dimethyl-but-2-en werden bei Raumtemperatur 528 mg (1.07 mmol) R9-1-S1 vorgelegt. Nun wird langsam eine Lösung von 893 mg (9.82 mmol) NaClO2 und 893 mg (7.41 mmol) NaH2PO4 in 8.9 mL Wasser zugetropft.528 mg (1.07 mmol) of R9-1-S1 are placed in 22.3 mL of tert-butanol and 5.4 mL of 2,3-dimethyl-but-2-ene at room temperature. A solution of 893 mg (9.82 mmol) NaClO 2 and 893 mg (7.41 mmol) NaH 2 PO 4 in 8.9 mL water is slowly added dropwise.

Nach ca. 5 h wird die Lösung mit verd. HCl leicht angesäuert und fünf mal mit CH2Cl2 extrahiert. Die organische Phase wird über Magnesiumsulfat getrocknet, filtriert und eingeengt. Das Rohprodukt wird über eine 1 : 1-Hex/EE-Kieselgelsäule chromatographiert. Es wurden 527 mg (96.7%) R10-1-S1 als weiße kristalline Verbindung erhalten.
After approx. 5 h the solution is slightly acidified with dil. HCl and extracted five times with CH 2 Cl 2 . The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product is chromatographed on a 1: 1 hex / EA silica gel column. 527 mg (96.7%) of R10-1-S1 were obtained as a white crystalline compound.

1H-NMR (250 MHz, CDCl3) von R10-1-S1: δ in ppm =
0.03 (s, 3H, Si-CH3); 0.06 (s, 3H, Si-CH3); 0.82 (d, J = 6.9 Hz, 3H, 5'-CH3); 0.85 (s, 9H, -C(CH3)3); 1.12 (s, 3H, 4a-CH3); 1.15 (d, J = 7.2 Hz, 3H, 7-H); 1.22 (s, 3H,4b-CH3); 2.03 (mc, 1H, 5'-H); 2.31 (dd, J = 16.5, 6.6 Hz, 1H, 2a-H); 2.46 (dd, J = 16.2, 3.6 Hz, 1H, 2b-H); 3.28 (qd, J = 6.9, 3.0 Hz, 1H, 6-H); 3.49 (t, J- 11.0 Hz, 1H, 6a'-H); 3.76 (s, 3H, OCH3); 3.77 (dd, J = 9.9, 3.0 Hz, 1H, 4'- H); 4.08 (dd, J = 11.3, 4.7 Hz, 1H, 6b-H); 4.57 (dd, J = 6.6, 3.6 Hz, 1H, 3-H); 5.39 (s, 1H, -O2CHAr); 6.84 (mc, 2H, CHarom); 7.34 (mc, 2H, CHarom).
 1 H-NMR (250 MHz, CDCl 3 ) of R10-1-S1: δ in ppm =
0:03 (s, 3H, Si-CH 3); 0:06 (s, 3H, Si-CH 3); 0.82 (d, J = 6.9 Hz, 3H, 5'-CH 3 ); 0.85 (s, 9H, -C (CH 3) 3); 1.12 (s, 3H, 4-CH 3); 1.15 (d, J = 7.2 Hz, 3H, 7-H); 1.22 (s, 3H, 4b-CH 3); 2.03 (mc, 1H, 5'-H); 2.31 (dd, J = 16.5, 6.6 Hz, 1H, 2a-H); 2.46 (dd, J = 16.2, 3.6 Hz, 1H, 2b-H); 3.28 (qd, J = 6.9, 3.0 Hz, 1H, 6-H); 3.49 (t, J-11.0 Hz, 1H, 6a'-H); 3.76 (s, 3H, OCH 3 ); 3.77 (dd, J = 9.9, 3.0 Hz, 1H, 4'-H); 4.08 (dd, J = 11.3, 4.7 Hz, 1H, 6b-H); 4.57 (dd, J = 6.6, 3.6 Hz, 1H, 3-H); 5:39 (s, 1H, CHAr 2 -O); 6.84 (mc, 2H, CH aroma ); 7.34 (mc, 2H, CH aroma ).

13C-NMR (62.5 MHz, CDCl3): δ in ppm =
11.6; 12.5; 18.0; 19.1; 22.5; 25.8; 31.3; 39.2; 43.2; 53.5; 55.1; 72.7; 72.9; 82.1; 100.6; 113.4; 127.1; 130.7; 159.6; 176.8; 214.1.
 13 C-NMR (62.5 MHz, CDCl 3 ): δ in ppm =
11.6; 12.5; 18.0; 19.1; 22.5; 25.8; 31.3; 39.2; 43.2; 53.5; 55.1; 72.7; 72.9; 82.1; 100.6; 113.4; 127.1; 130.7; 159.6; 176.8; 214.1.

IR(KBr-Film): ν in cm-1 =
2959 s; 2936 s; 2883 m; 2855 m; 1707 vs; 1616 m; 1588 w; 1519 s; 1464 m; 1429 w; 1388 m; 1371 w; 1360 w; 1313 m; 1251 vs; 1220 w; 1172 m; 1160 w; 1123 m; 1101 s; 1077 m; 1041 m; 1029 m; 1010 m; 996 m; 982 m; 952 w; 939 w; 836 s; 776 s; 687 w; 670 w.
IR (KBr film): ν in cm -1 =
2959 s; 2936 s; 2883 m; 2855 m; 1707 vs; 1616 m; 1588 w; 1519 s; 1464 m; 1429 w; 1388 m; 1371 w; 1360 w; 1313 m; 1251 vs; 1220 w; 1172 m; 1160 w; 1123 m; 1101 s; 1077 m; 1041 m; 1029 m; 1010 m; 996 m; 982 m; 952 w; 939 w; 836 s; 776 s; 687 w; 670 w.

MS (EI, 70 eV, 280°C): m/e=
509[M⁺]; 508(M-H); 451; 315; 297; 266; 227; 207; 187; 171; 153; 145; 137; 135; 121; 101; 83; 75; 50.
MS (EI, 70 eV, 280 ° C): m / e =
509 [M⁺]; 508 (MH); 451; 315; 297; 266; 227; 207; 187; 171; 153; 145; 137; 135; 121; 101; 83; 75; 50.

C27H44O7Si: (M= 508.7 g.mol-1) EA:
ber.: C: 63.75% H: 8.72%
gef.: C: 63.63% H: 8.91%C 27 H 44 O 7 Si: (M = 508.7 g.mol -1 ) EA:
calc .: C: 63.75% H: 8.72%
found: C: 63.63% H: 8.91%

Claims (10)

1. Verbindungen der allgemeinen Formel I
worin
R1 Wasserstoff; C1-C6-Alkyl, oder Benzyl und
X OH, Halogen, -SO2Ph, -SO2-B oder
mit
R2 in der Bedeutung von Wasserstoff oder Methyl,
B in der Bedeutung von C1-C4-Alkyl oder C1-C4-Perfluoralkyl und
n in der Bedeutung von 0 oder 1
bedeuten.1. Compounds of the general formula I
wherein
R 1 is hydrogen; C 1 -C 6 alkyl, or benzyl and
X OH, halogen, -SO 2 Ph, -SO 2 -B or
With
R 2 is hydrogen or methyl,
B in the meaning of C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl and
n has the meaning of 0 or 1
mean. 2. Verbindungen der allgemeine Formel Ia
worin
R1 Wasserstoff; C1-C6-Alkyl, oder Benzyl,
R6 (R8)(R9)(R10)Si oder ein gegebenenfalls substituierter Benzylrest
R7 eine beliebige chelatisierungsfähige Schutzgruppe
X OH, Halogen, -SO2Ph, -SO2-B oder
mit
R2 in der Bedeutung von Wasserstoff oder Methyl,
B in der Bedeutung von C1-C4-Alkyl oder C1-C4-Perfluoralkyl und
n in der Bedeutung von 0 oder 1
bedeuten. 2. Compounds of the general formula Ia
wherein
R 1 is hydrogen; C 1 -C 6 alkyl, or benzyl,
R 6 (R 8 ) (R 9 ) (R 10 ) Si or an optionally substituted benzyl radical
R 7 is any protective group capable of chelation
X OH, halogen, -SO 2 Ph, -SO 2 -B or
With
R 2 is hydrogen or methyl,
B in the meaning of C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl and
n has the meaning of 0 or 1
mean. 3. Verbindungen der allgemeinen Formel II
worin
Y OH, Brom, Iod
R3 Wasserstoff oder Methyl,
R4 eine beliebige chelatisierungsfähige Schutzgruppe und
R5 C1-C4-Alkyl bedeuten.3. Compounds of the general formula II
wherein
Y OH, bromine, iodine
R 3 is hydrogen or methyl,
R 4 is any protective group capable of chelation and
R 5 is C 1 -C 4 alkyl. 4. Verbindung der allgemeinen Formel III
worin
R1 Wasserstoff, C1-C6-Alkyl, oder Benzyl,
R3 Wasserstoff oder Methyl,
R4 eine beliebige chelatisierungsfähige Schutzgruppe und
R5 C1-C4-Alkyl bedeuten.4. Compound of the general formula III
wherein
R 1 is hydrogen, C 1 -C 6 alkyl, or benzyl,
R 3 is hydrogen or methyl,
R 4 is any protective group capable of chelation and
R 5 is C 1 -C 4 alkyl. 5. Die Verbindung der Formel IV
worin PMB für p-Methoxybenzyl steht. 5. The compound of formula IV
where PMB stands for p-methoxybenzyl. 6. Die Verbindung der Formel V
worin PMP für p-Methoxyphenyl steht.6. The compound of formula V
where PMP stands for p-methoxyphenyl. 7. Die Verbindung der Formel VI
worin PMP für p-Methoxyphenyl steht.7. The compound of formula VI
where PMP stands for p-methoxyphenyl. 8. Die Verbindung der Formel VII
worin PMP für p-Methoxyphenyl und TBS für tert.Butyldimethylsilyl stehen.8. The compound of formula VII
where PMP is p-methoxyphenyl and TBS is tert-butyldimethylsilyl. 9. Verbindungen der Formel (VIII),
worin PMP für p-Methoxyphenyl und TBS für tert.Butyldimethylsilyl stehen. 9. Compounds of the formula (VIII),
where PMP is p-methoxyphenyl and TBS is tert-butyldimethylsilyl. 10. Verfahren zur Herstellung der Verbindung der Formel (VIII)
dadurch gekennzeichnet, daß in an sich bekannter Weise in einem Schritt 1
die Hydroxyfunktion von Methyl-3-hydroxy-(2S)-methylpropionat(IX) als p- Methoxybenzylether durch Umsetzung mit p-Methoxy-benzyl-2,2,2- trichloracetimidat(PMBTCAI) geschützt wird (a), der Ester mit Diisopropylaluminiumhydrid unter bekannten Bedingungen zum Alkohol reduziert wird (b)und der Alkohol anschließend mit Oxalylchlorid in DMSO zum Aldehyd (X) oxidiert wird und
in einem Schritt 2
der erhaltene Aldehyd (X) mit dem aus Lithimdiisopropylamid und 2,2-Dimethyl-1- hexen-4-on erzeugten Lithiumenolat umgesetzt wird zu Verbindung (IV) und
in einem Schritt 3
die sekundäre Alkoholfunktion des erhaltenen Ketons (IV)gemeinsam mit der primären Alkoholfunktion als Benzylidenacetal geschützt wird (e), die terminale Vinylgruppe mit Ozon gespalten wird und
in einem Schritt 4
der erhaltene Aldehyd (V) mit Allylboran (g) in den Allylalkohol VI) überführt wird und
in einem Schritt 5
die Alkoholfunktion mit Tertiärbutyldimethylsilyltriflat in Methylenchlorid umgesetzt wird (h), die terminale Vinylgruppe mit Ozon gespalten wird (i), und der Aldehyd mit Natriumchlorit, Natriumdihydrogenphosphat, 2,3-dimethyl-but-2-en zur Carbonsäure (VIII) oxidiert wird, die gegebenenfalls in einen Ester überführt werden kann.10. Process for the preparation of the compound of formula (VIII)
characterized in that in a manner known per se in a step 1
the hydroxy function of methyl 3-hydroxy- (2S) -methylpropionate (IX) as p-methoxybenzyl ether is protected by reaction with p-methoxy-benzyl-2,2,2-trichloroacetimidate (PMBTCAI) (a), the ester with diisopropyl aluminum hydride is reduced to the alcohol under known conditions (b) and the alcohol is then oxidized to the aldehyde (X) with oxalyl chloride in DMSO and
in a step 2
the aldehyde (X) obtained is reacted with the lithium enolate produced from lithimdiisopropylamide and 2,2-dimethyl-1-hexen-4-one to give compound (IV) and
in a step 3
the secondary alcohol function of the ketone (IV) obtained is protected together with the primary alcohol function as benzylidene acetal (e), the terminal vinyl group is cleaved with ozone and
in a step 4
the aldehyde (V) obtained is converted into the allyl alcohol VI) with allylborane (g) and
in a step 5
the alcohol function is reacted with tertiary butyldimethylsilyl triflate in methylene chloride (h), the terminal vinyl group is cleaved with ozone (i), and the aldehyde is oxidized with sodium chlorite, sodium dihydrogen phosphate, 2,3-dimethyl-but-2-ene to the carboxylic acid (VIII), which can optionally be converted into an ester.
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