WO2004009574A1 - Synthesis of discodermolide - Google Patents

Synthesis of discodermolide Download PDF

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Publication number
WO2004009574A1
WO2004009574A1 PCT/EP2003/007940 EP0307940W WO2004009574A1 WO 2004009574 A1 WO2004009574 A1 WO 2004009574A1 EP 0307940 W EP0307940 W EP 0307940W WO 2004009574 A1 WO2004009574 A1 WO 2004009574A1
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Prior art keywords
formula
hydroxy group
protecting groups
alkyl
hydrogen
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PCT/EP2003/007940
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French (fr)
Inventor
Gordon Florence
Guido Koch
Olivier Loiseleur
Stuart John Mickel
Ian Paterson
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Novartis Ag
Novartis Pharma Gmbh
Cambridge University Technical Services Ltd.
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Priority claimed from GB0223731A external-priority patent/GB0223731D0/en
Application filed by Novartis Ag, Novartis Pharma Gmbh, Cambridge University Technical Services Ltd. filed Critical Novartis Ag
Priority to AU2003251431A priority Critical patent/AU2003251431A1/en
Publication of WO2004009574A1 publication Critical patent/WO2004009574A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones

Definitions

  • the invention relates to a process for preparing discodermolide, for preparing intermediates for the manufacture of discodermolide and discodermolide analogues and to the intermediates obtained during the process.
  • (+)-Discodermolide is a poly etide natural product that was isolated from extracts of the marine sponge Discodermolide dissoluta by researchers at the Harbor Branch Oceano- graphic Institution [S.P. Gunasekera et al., J. Org. Chem. 1990;55:4912-15 (published erratum appears in J. Org. Chem. 1991:56:1346)].
  • Discodermolide lacks obvious structural resemblance to paclitaxel, yet it shares with paclitaxel (the active substance in the drug Taxol®) the ability to stabilize microtuhu)es. Pac ⁇ itaxel has proven to be useful in treating some types of cancer in clinical practice.
  • Discodermolide binds to tubulin competitively with paclitaxel and was shown to have utility against hyperproliferative disorders (see, e.g., WO 97/20835).
  • Future development of discodermolide or structurally related analogues is hindered by the lack of a natural source that could provide greater amounts of the compound, since naturally occurring discodermolide is scarce and harvesting the producing organism presents logistical problems. Accordingly, there is a need for efficient processes for the manufacture of discodermolide and analogues thereof and for novel intermediates for such processes of manufacture which processes and intermediates enable the manufacture of commercially acceptable quantities of discodermolide and structurally related analogues.
  • the present invention relates to a process for preparing a lactone of formula I
  • R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group and R 4 is H 2 NC(0)-, in which process in a first step a triene of formula V
  • Ri, R 2 , R 3 and R 4 are protecting groups for a hydroxy group, characterized in that R ⁇ and R 4 can be split off under reaction conditions that do not result in cleavage of any of the protecting groups R 2 or R 3> is prepared by the reaction of a vinyl iodide of formula VI,
  • R 1 and R 2 are different protecting groups for a hydroxy group, characterized in that Ri can be split off under reaction conditions that do not result in the cleavage of the protecting group R 2 , with a diene of formula VII,
  • R 3 and R 4 are different protecting groups for a hydroxy group and X is a leaving group, characterized in that R 4 can be split off under reaction conditions that do not result in the cleavage of the protecting group R 3 ,
  • the protecting groups Ri and R 4 are split off to provide a compound of formula V, wherein Ri and R 4 are hydrogen, and R 2 and R 3 are identical or different protecting groups for a hydroxy group,
  • R 4 is hydrogen, and R 2 and R 3 are identical or different protecting groups for a hydroxy group,
  • R 2 and R are identical or different protecting groups for a hydroxy group and R 4 is hydrogen
  • ketone of formula 11 is reacted with Cl 3 C(0)NCO in the presence of neutral Al 2 0 3 to provide a ketone of formula II, wherein R 2 and R 3 are identical or different protecting groups for a hydroxy group and R 4 is H 2 NC(0)-,
  • R s is a protecting group for a hydroxy group
  • R represents
  • R 6 -0-N(R 7 )- wherein R 6 and R 7 are independently of each other alkyl or together represent a radical -(CH 2 ) P - wherein p is 3, 4 or 5,
  • R 9 represents alkyl or aryl
  • R ⁇ 0 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the aldehyde of formula III via the nitrogen atom, to provide a tetraene of formula IV
  • R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group
  • R 4 is hydrogen or H 2 NC(0)-
  • R represents
  • R 6 -0-N(R 7 )- wherein R 6 and R 7 are independently of each other alkyl or together represent a radical -(CH 2 ) P - wherein p is 3, 4 or 5,
  • the obtained compounds of formula I wherein R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group and R 4 is H 2 NC(0)-, can be transformed into a compound of formula I, wherein R 2 , R 3 and R 5 are hydrogen and R is H 2 NC(O)- ((+)- discodermolide), by cleavage of the protecting groups R 2 , R 3 and R 5 under suitable conditions known as such, e.g. by treatment with hydrogenchloride in a lower alkanol if R 2 , R 3 and R 5 represent tri-Iower alkyl silyl radicals.
  • the hydroboration on the substrates of formula XII proceeds in good yields and with >95% diastereoselectivity.
  • This approach avoids the expensive Roche ester, which is employed frequently in methods described in the state of the art.
  • all the intermediates to the lactones of Example 1 and 2 are crystalline, which is also the case for the lactone of Example 1. Crystallinity of the intermediates in the early stage of the total synthesis constitutes a major advantage as it much simplifies the purifications and avoids costly chromatographies.
  • the access to the common intermediates of Example 1 and 2 is shorter and/or more practical as well as higher yielding than the synthesis of common precursors described in the prior art.
  • a further advantage is that the chiral auxiliary, e.g.
  • ( ?)-4-isopropyl-5,5-diphenylpropionyloxazolidin-2-one can be efficiently recycled by precipitation and filtration during the lactonization reaction.
  • a common building block that can be employed in the present approach is the diol of formula XXXVIII, wherein Ri represents p-methoxybenzyl (see below), which is also crystalline and can be obtained from the commercially available starting material of formula XXXIII in a 5-step sequence which can be performed with minimal chromatographic purification.
  • protecting groups for a hydroxy group refers to acid labile, fluoride labile and / or oxidatively labile protecting groups for a hydroxy group, which groups are known as such. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
  • Preferred protecting groups are silyl ethers which are acid labile or fluoride labile like tert-butyl-dimethyl-silyl (TBDMS) ether, triethylsilyl (TES) ether, triisopropylsilyl (TIPS) ether, diethylisopropylsilyl (DEIPS) ether, isopropyldimethylsilyl (IPDMS) ether or thexyldimethylsilyl (TDS) ether; esters which are acid labile like pivaloate ester; substituted benzyl ethers which are oxidatively labile like 3,4-dimethoxybenzyl (DMPM) ether or p-methoxybenzyl (PMB) ether; substituted ethylethers which are acid labile like 1- ethoxyethyl (EE) ether, 1-(2-(trimethylsi!yl)ethoxy)ethyl (S
  • the prefix "lower” means that the respective moiety preferably has up to and including a maximum of 7 carbon atoms, more preferably up to 4 carbon atoms.
  • Alkyl is preferably lower alkyl which can be linear or branched and is especially methyl, ethyl; n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or, preferably, methyl or ferf-butyl.
  • Aryl is an aromatic radical which is bound to the molecule via a bond located at an aromatic ring carbon atom of the radical.
  • aryl is an aromatic radical having 6 to 14 carbon atoms and denotes especially monocyclic aryl, in particular phenyl, or bicyclic aryl, in particular naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, and is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from amino, halogen, lower alkyl, hydroxy, etherified or lower alkoxy, nitro, cyano, carboxy, lower alkanoyl, benzoyl and carbamoyl.
  • Aryl is more preferably phenyl.
  • the protecting groups Rt and R 4 can be identical or different to each other and can be split off under reaction conditions under which the protecting groups R 2 and R 3 remain in place.
  • Ri and R 4 together with the oxygen atom to which they are attached independently of each other form a TES ether; a trityl ether; an acid labile substituted ethyl ether, in particular SEE ether, MIP-OR ether or MBE ether; an oxidatively labile substituted benzyl ether, in particular PMB ether or DMPM ether; or an acid labile substituted methyl ether, in particular a THP ether.
  • R 2 and R 3 each represent a PMB radical and Ri and R 4 together with the oxygen atom to which they are attached independently of each other form a silyl ether which is acid labile or fluoride labile, especially a TBDMS ether, TIPS ether, DEIPS ether, IPDMS ether or TDS ether; a substituted ethyl ether which is acid labile, especially EE ether or 2-trimethylsilylethyl ether; a substituted methyl ether, especially MEM ether, MOM ether, BOM ether, PMBM ether, ferf-butoxymethyl ether, siloxymethyl ether or SEM ether; or an acid labile ester, especially a pivaloate ester.
  • a silyl ether which is acid labile or fluoride labile, especially a TBDMS ether, TIPS ether, DEIPS ether, IPDMS ether or TDS ether
  • Ri and R 4 each represent a TES radical and R 2 and R 3 together with the oxygen atom to which they are attached are preferably employed as silyl ethers which are acid labile or fluoride labile, especially TBDMS ether, TIPS ether, DEIPS ether, IPDMS ether and TDS ether; esters which are acid labile, especially pivaloate ester; benzyl ethers which are oxidatively labile, especially DMPM ether or PMB ether; substituted ethylethers which are acid labile or fluoride labile, especially 1-ethoxyethyl ether and 2-trimethylsilylethyl ether; substituted methyl ethers which are acid labile or fluoride labile, especially MEM ether, MOM ether, BOM ether, PMBM ether, te/ -butoxymethyl ether, siloxymethyl ether or SEM ether.
  • silyl ethers which are acid labile
  • R 5 is preferably a silyl ether, in particular, selected from TES, TBDMS, TIPS, DEIPS, IPDMS and TDS ether; a pivaloate ester; a substituted benzyl ether, in particular, selected from PMB and DMPM ether; a substituted ethyl ether, in particular, selected from EE, SEE, MIP-OR, MBE and 2-trimethylsilylethyl ether; or a substituted methyl ether, in particular, selected from MEM, MOM, BOM, PMBM, terf-butoxymethyl, THP, siloxymethyl and SEM ether.
  • R 5 is TBDMS.
  • R g is preferably methyl, isopropyl, benzyl or phenyl.
  • R 10 and Rn are preferably both phenyl.
  • R is preferably (a) R 6 -0-N(R 7 )- wherein R 6 and R 7 are independently of each other lower alkyl or together represent a radical -(CH 2 ) P - wherein p is 3, 4 or 5, (b) R 8 -O-, wherein R 8 represents lower alkyl, or (c) a substructure of formula Ilia wherein R 9 represents lower alkyl or C 6 -C M aryl, R w and Rn represent independently of each other hydrogen, lower alkyl or C 6 - C ⁇ 4 aryl, and which substructure is bound to the rest of the molecula via the nitrogen atom.
  • R is R 6 -0-N(R 7 )- wherein R 6 and R 7 are independently of each other lower alkyl or (c) a substructure of formula Ilia wherein R 9 represents lower alkyl or phenyl, R ⁇ 0 and Rn represent independently of each other hydrogen, lower alkyl or phenyl.
  • X is preferably a halogen selected from chloride, bromide and iodide. Most preferably, X is iodide.
  • the present invention relates furthermore to a process for preparing a triene of formula V wherein
  • R- and R 4 are hydrogen
  • R 2 and R 3 are identical or different protecting groups for a hydroxy group, in which process a vinyl iodide of formula VI, wherein Ri and R 2 are different protecting groups for a hydroxy group, characterized in that
  • Ri can be split off under reaction conditions that do not result in splitting off the protecting group R 2 , is reacted with a diene of formula VII, wherein R 3 and R 4 are different protecting groups for a hydroxy group, characterized in that
  • R 4 can be split off under reaction conditions that do not result in splitting off the protecting group R 3 , and wherein afterwards, the protecting groups Ri and R 4 are split off simultaneously or sequentially.
  • the present invention relates to a vinyl iodide of formula VI wherein Ri and R 2 are different protecting groups for a hydroxy group, characterized in that R can be split off under reaction conditions that do not result in splitting off the protecting group R 2 , especially a vinyl iodide of formula VI wherein Ri is triethylsilyl and R 2 is tert-butyl-dimethyl-silyl, and the salts thereof, if applicable.
  • the present invention relates to a diene of formula VII, wherein R 3 and R 4 are different protecting groups for a hydroxy group, characterized in that R 4 can be split off under reaction conditions that do not result in splitting off the protecting group R 3 , especially a diene of formula VII wherein R 4 is triethylsilyl and R 3 is tert-butyl-dimetbyl-silyJ, and the salts thereof, if applicable.
  • the present invention provides a process for preparing a tetraene of formula IV wherein
  • R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group
  • R 4 is hydrogen or H 2 NC(0)-
  • R represents
  • R 6 -0-JM(R 7 )- wherein R 6 and R 7 are independently of each other alkyl or together represent a radical -(CH 2 ) P - wherein p is 3, 4 or 5,
  • R 4 is hydrogen or H 2 NC(0)-, is reacted with an aldehyde of formula III wherein
  • R 5 is a protecting group for a hydroxy group
  • R represents
  • R 6 -0-N(R 7 )- wherein R 6 and R 7 are independently of each other alkyl or together represent a radical -(CH 2 ) P - wherein p is 3, 4 or 5,
  • the present invention relates to a tetraene of formula IV wherein R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group, R. 1 is hydrogen or H 2 NC(0)-, R represents
  • R 6 -0-N(R 7 )- wherein R 6 and R 7 are independently of each other alkyl or together represent a radical -(CH 2 ) P - wherein p is 3, 4 or 5,
  • Another aspect of the present invention is a process for preparing a lactone of formula I, wherein R 2 , R 3 and R 5 are hydrogen and R 4 is H 2 NC(0)- ((+)-discodermolide), wherein a ketone of formula II wherein R 2 and R3 are identical or different protecting groups for a hydroxy group and R t is hydrogen or H 2 NC(0)-, is reacted with an aldehyde of formula III wherein R 5 is a protecting group for a hydroxy group, and R represents
  • R 6 -0-N(R 7 )- wherein R 6 and R 7 are independently of each other alkyl or together represent a radical -(CH 2 ) P - wherein p is 3, 4 or 5,
  • R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group
  • R 4 is hydrogen or H 2 NC(O)-
  • R represents
  • R 6 -0-N(R 7 )- wherein R 6 and R 7 are independently of each other alkyl or together represent a radical -(CH 2 ) P - wherein p is 3, 4 or 5,
  • a further aspect of the present invention is a process for preparing a lactone of formula IB
  • R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group and R is H 2 NC(0)-, wherein in a first step the keto group in a tetraene of formula IV wherein
  • R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group
  • R 4 is hydrogen or H 2 NC(0)-
  • R represents
  • R 6 -0-N(R 7 )- wherein R 6 and R 7 are independently of each other alkyl or together represent a radical -(CH 2 ) P - wherein p is 3, 4 or 5,
  • R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group
  • R 4 is hydrogen or H 2 NC(O)-
  • R represents
  • R 6 -0-N(R 7 )- wherein R 6 and R 7 are independently of each other alkyl or together represent a radical -(CH 2 ) P - wherein p is 3, 4 or 5,
  • a reducing agent capable that provides selectively a diol of formula (7S)-LV as the major product
  • R 2 and R 3 are identical or different protecting groups for a hydroxy group and R 4 is hydrogen or H 2 NC(O)-.
  • the present invention furthermore provides the. ⁇ -valerolacton of the formula VIII
  • All process steps described herein can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralisiing agents, for example ion exchangers, typically cation exchangers, for example in the H + form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from -100°C to about 190°C, preferably from about -80°C to about 150°C, for example at -80 to -60°C, at room temperature, at - 20 to 40°C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.
  • solvents or diluents preferably such as are inert to the rea
  • the solvents from which those can be selected which are suitable for the reaction in question include for example water, esters, typically lower alkyl-lower alkanoates, e.g diethyl acetate, ethers, typically aliphatic ethers, e.g. diethylether, or cyclic ethers, e.g. tetrahydrofuran, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically methanol, ethanol or 1- or 2-propanol, nitrites, typically acetonitrile, halogenated hydrocarbons, typically dichloromethane, acid amides, typically dimethylformamide, bases, typically heterocyclic nitrogen bases, e.g.
  • carboxylic acids typically lower alkanecarboxylic acids, e.g. acetic acid, carboxylic acid anhydrides, typically lower alkane acid anhydrides, e.g. acetic anhydride, cyclic, linear, or branched hydrocarbons, typically cyclohexane, he- xane, or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the process.
  • solvent mixtures may also be used in processing, for example through chromatography or distribution.
  • Salts of the compounds mentioned herein with a salt-forming group may be prepared in a manner known perse. Acid addition salts may thus be obtained by treatment with an acid or with a suitable anion exchange reagent. Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • suitable basic agents for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • Stereoisomeric mixtures e.g. mixtures of diastereomers
  • Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of one of the starting compounds, the intermediates or in a compound of formula I itself.
  • Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
  • the triene of formula V wherein Ri, R 2) R 3 and R are identical or different protecting groups for a hydroxy group, characterized in that Ri and f ⁇ t can be split off under reaction conditions that do not result in splitting off the protecting group R 2 and R 3 , can be prepared by a Suzuki coupling reaction of a vinyl iodide of formula VI, wherein Ri and R 2 are different protecting groups for a hydroxy group, characterized in that Ri can be split off under reaction conditions that do not result in splitting off the protecting group R 2 , with a compound of formula VII, wherein R 3 and R 4 are different protecting groups for a hydroxy group, characterized in that R 4 can be split off under reaction conditions that do not result in splitting off the protecting group R 3 , which compound is first reacted with ferf-butyl lithium in an inert solvent, e.g.
  • the protecting groups Ri and R can be split off by reactions known in the art providing a diol of formula V, wherein Ri and R 4 are hydrogen, and R 2 and R 3 are identical or different protecting groups for a hydroxy group.
  • the protection of hydroxy groups by protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981 , in "The Peptides”; Volume 3 (editors: E. Gross and J.
  • Ri and R 4 each represent a TES radical and R and R 3 together with the oxygen atom to which they are attached are TBDMS ethers
  • cleavage of the TES ethers without cleaving the TBDMS ethers can be achieved by hydrolysis of the compound of formula V in a suitable solvent like tetrahydrofurane or a lower alkanol or, preferably, a mixture thereof, at a temperature between 0 °C and 50 °C, for example, room temperature, by addition of water and chloroacetic acid.
  • An aldehyde of formula IX wherein R is hydrogen and R 2 and R 3 are identical or different protecting groups for a hydroxy group can be obtained by oxidation of a diol of formula V wherein Ri and R are hydrogen, and R 2 and R 3 are identical or different protecting groups for a hydroxy group by sequentielly reacting the diol of formula V, with 2,2,6,6-tetramethyl- piperidine 1-oxyl (TEMPO) and iodobenzene diacetate, e.g., in dichloromethane at a temperature between - 5°C and + 5 °C, e.g. 0 °C.
  • TEMPO 2,2,6,6-tetramethyl- piperidine 1-oxyl
  • iodobenzene diacetate e.g., in dichloromethane at a temperature between - 5°C and + 5 °C, e.g. 0 °C.
  • a ketone of formula II wherein R 2 and R 3 are identical or different protecting groups for a hydroxy group and R 4 is hydrogen can be obtained by the reaction of the aldehyde of formula IX, wherein R 4 is hydrogen and R 2 and R 3 are identical or different protecting groups for a hydroxy group, with a phosphonate ester of formula X in the presence of a suitable base, e.g. potassium carbonate together with 18-crown-6, in a suitable solvent, like benzene or toluene together with HMPA, at a temperature between 5 °C and 40 °C, e.g. 20 °C to 25 °C, for 1 to 5 hours.
  • a suitable base e.g. potassium carbonate together with 18-crown-6
  • a suitable solvent like benzene or toluene together with HMPA
  • such ketone of formula II wherein R 4 is hydrogen can be reacted in CH 2 CI 2 with CI 3 CNCO at a temperature between 5 °C and 40 °C, e.g. 20 °C to 25 °C, for 2 to 6 hours to provide a ketone of formula II, wherein R 2 and R 3 are identical or different protecting groups for a hydroxy group and R 4 is CI 3 CN(H)C(0)-.
  • R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group
  • R 4 is hydrogen or H 2 NC(0)-
  • R represents (a) R 6 -0-N(R 7 )- wherein Re and R 7 are independently of each other alkyl or together represent a radical -(CH 2 ) P - wherein p is 3,
  • Suitable as tertiary amine is especially ammonia substituted by three radicals selected independently of one another from alkyl, especially lower alkyl, such as methyl or ethyl, and cycloalkyl having from 3 to 7 carbon atoms, especially cyclohexyl, for example N,N-dimethyl-N-cyclohexylamine, N-ethyl-N,N-diisopropylamine or triethylamine, or, furthermore, also pyridine, N-methylmorpholine or 4-dimethylaminopyridine.
  • the preparation of the compounds of formula III, VI and VII can be based on the common precursor of formula XIII and/or the common precursor of formula XVI.
  • R has the meaning as defined above for a compound of formula III, with a mixture of a suitable base, e.g. a tertiary amine as defined above, and a di-lower alkyl boro triflate in a suitable solvent, in particular dichloromethane, at a temperature between -70 °C and -85 °C, e.g. about -78 °C, and adding at the same temperature to the obtained intermediate over a period of between 15 and 45 minutes, e.g. 30 minutes, a solution of methacrolein in the same or a different solvent, and stirring thereafter for about 30 minutes to 90 minutes, e.g. 60 minutes, the mixture at a temperature between -5 °C and +5 °C, e.g. about 0 °C; in order to obtain a compound of formula XII,
  • R has the meaning as defined above for a compound of formula III, and transforming the compound of formula Xll in a second step via a hydroboration reaction into the diol of formula XIII as defined above, e.g. by adding the compound of formula Xll in a suitable inert solvent, e.g. tetrahydrofurane, dropwise to a solution of a suitable borane, e.g. thexyl borane, in a suitable inert solvent, e.g. also tetrahydrofurane, at a temperature between -5 °C and +5 °C, e.g. about 0 °C, over a period of between 20 and 60 minutes, e.g. about 40 minutes.
  • a suitable inert solvent e.g. tetrahydrofurane
  • a R 2 -triflate wherein R 2 is a protecting group for a hydroxy group, is added dropwise over a period of between 20 and 60 minutes, e.g. about 35 minutes, at a temperature between -5 °C and +5 °C, e.g. about 0 °C, to a solution of the compound of formula XIII, wherein R has the meaning as defined above for a compound of formula III, in a suitable inert solvent, e.g. dichloromethane, and 2,6-lutidine, furnishing a compound of formula XIV,
  • a suitable inert solvent e.g. dichloromethane, and 2,6-lutidine
  • R has the meaning as defined above for a compound of formula Iff and R 2 is a protecting group for a hydroxy group.
  • R 2 is a protecting group for a hydroxy group and R has the meaning as defined above for a compound of formula III.
  • R 2 is a protecting group for a hydroxy group
  • R 2 can be obtained by the reaction of a compound of formula XV, wherein R 2 is a protecting group for a hydroxy group and R has the meaning as defined above for a compound of formula III, with a catalytic amount of a potassium alcoholate, e.g. potassium tert-butanolate, in a suitable solvent, e.g. tetrahydrofurane, at a temperature between about -10 °C and + 10 °C, e.g. 0 °C.
  • a potassium alcoholate e.g. potassium tert-butanolate
  • suitable solvent e.g. tetrahydrofurane
  • the common precursor of formula XV can be employed to furnish different fragments of the final compound of formula I.
  • the radical R 5 in the aldehyde of formula III is identical to the radical R 2 in the compound of formula XV.
  • the aldehyde of formula III wherein R s is a protecting group for a hydroxy group, and R has the meaning as given above, can be obtained in one step by oxidation of the compound of formula XV wherein R 2 is a protecting group for a hydroxy group and R has the meaning as defined above for a compound of formula III.
  • the oxidation of the alcohol function in the compound of formula XV to the aldehyde function in aldehyde of formula III can be achieved, e.g., by oxidation with Collin's reagent , eerie ammonium nitrate (for reaction conditions see, e.g. Trahanovsky et al, J. Chem. Soc.
  • N-methyl-morpholineoxide in the presence of a suitable Ru complex (for reaction conditions see, e.g. Sharpless et al, Tetrahedron Lett. 2503, 1976), and in particular, with DMSO in conjunction with a further suitable reagents, like acetic anhydride, oxalyl chloride, or, especially, a S0 3 -pyridine complex in the presence of a tertiary amine as defined above, preferably triethylamine.
  • the latter reaction is preferably carried out in a suitable inert solvent, e.g. dichloromethane, for a period of between 2 and 4 hours, e.g. about 3 hours, at a temperature between -5 °C and +5 °C, e.g. about 0 °C.
  • a solution of a suitable Grignard reagent e.g.
  • isopropylmagnesium chloride in a suitable inert solvent, e.g., tetrahydrofurane, is added dropwise over a period of between 15 and 45 minutes, e.g. about 30 minutes, and stirred at the same temperature for a period of between 5 and 30 minutes, e.g. about 15 minutes, providing a hydroxamic acid of formula XVII
  • R 2 is a protecting group for a hydroxy group.
  • the hydroxamic acid of formula XVII wherein R 2 is a protecting group for a hydroxy group, solved in a suitable inert solvent, e.g., dimethylformamide, is reacted at a temperature between -5 °C and +5 °C, e.g. about 0 °C, for a period of between 2 and 4 hours, e.g. about 3 hours, in the presence of imidazole and dimethylaminopyridine with R Y.
  • R is is a protecting group for a hydroxy group characterized in that Ri can be split off under reaction conditions that do not result in splitting off the protecting group R 2
  • Y is a suitable leaving group, e.g. a halogenide like chloride or bromide, furnishing a hydroxamic acid of formula XVIII,
  • Ri and R 2 are protecting groups for a hydroxy group as defined above for a compound of formula VI.
  • a suitable inert solvent e.g. benzene or toluene
  • Ri and R 2 are protecting groups for a hydroxy group as defined above for a compound of formula VI.
  • aldehyde of formula XIX is subject of a Wittig reaction.
  • a suitable inert solvent e.g. tetrahydrofurane
  • a solution of sodium hexamethyldisilazan in a suitable inert solvent e.g. tetrahydrofurane
  • the common precursor of formula XVI can be employed to furnish different fragments of the final compound of formula I.
  • the radical R in the diene of formula VII is identical to the radical R 2 in the compound of formula XVI.
  • a solution of a suitable Grignard reagent e.g.
  • isopropylmagnesium chloride in a suitable inert solvent, e.g., tetrahydrofurane, is added dropwise over a period of between 15 and 45 minutes, e.g. about 30 minutes, and stirred at the same temperature for a period of between 5 and 30 minutes, e.g. about 15 minutes, providing a hydroxamic acid of formula XX
  • R 4 is a protecting group for a hydroxy group.
  • the alcohol function in the hydroxamic acid of formula XX is oxidized to the corresponding aldehyde.
  • the oxidation of the alcohol function in the compound of formula XX an be achieved, e.g., by oxidation with Collin's reagent , eerie ammonium nitrate (for reaction conditions see, e.g. Trahanovsky et al, J. Chem. Soc. 5777, 1965), N-methyl-morpholineoxide in the presence of a suitable Ru complex (for reaction conditions see, e.g. Sharpless et al, Tetrahedron Lett.
  • a further suitable reagents like acetic anhydride, oxalyl chloride, or, especially, a SO 3 -pyridine complex in the presence of a tertiary amine as defined above, preferably triethylamine.
  • the latter reaction is preferably carried out in a suitable inert solvent, e.g. dichloromethane, for a period of between 2 and 4 hours, e.g. about 3 hours, at a temperature between -5 °C and +5 °C, e.g. about 0 °C, providing a hydroxamic acid of formula XXI
  • R 4 is a protecting group for a hydroxy group.
  • R 4 is a protecting group for a hydroxy group, e.g., by a Wittig reaction, a Peterson olefination or, in particular, by a Nozaki-Hiyama-Kishi reaction.
  • a suitable inert solvent e.g., tetrahydrofurane
  • CrCI 2 and (1-halo- allyl)-tri-lower alkyl silane e.g.
  • the hydroxamic acid of formula XXII is transformed into the aldehyde of formula XXlll by reduction with a suitable reagent, e.g. by solving the hydroxamic acid of formula XXII in a suitable inert solvent, e.g. benzene or toluene, and reaction with Red-AITM in toluene, at a temperature between -30 °C and -50 °C, e.g. about -40 °C, for a period of between 60 and 90 minutes, e.g. about 75 minutes, and quenching the reaction by addition of aqueous potassium sodium tartrate at the same temperature, providing the aldehyde of formula XXlll,
  • a suitable inert solvent e.g. benzene or toluene
  • Red-AITM Red-AITM in toluene
  • the hydroxamic acid of formula XXII can be solved in a suitable inert solvent, e.g., tetrahydrofurane, and be treated at a temperature between -25 °C and -35 °C, e.g. about -30 °C, with diisobutylaluminium hydride furnishing also said aldehyde of formula XXlll.
  • a suitable inert solvent e.g., tetrahydrofurane
  • the aldehyde of formula XXlll wherein R is a protecting group for a hydroxy group
  • a compound of formula XI wherein R has the meaning as defined above for a compound of formula III, which compound of formula XI is first reacted with a mixture of a suitable base, e.g. a tertiary amine as defined above, and a di-lower alkyl boro triflate in a suitable solvent, in particular dichloromethane, both at a temperature between -70 °C and -85 °C, e.g. about -78 °C, providing a compound of formula XXIV,
  • a suitable base e.g. a tertiary amine as defined above
  • a di-lower alkyl boro triflate in a suitable solvent, in particular dichloromethane
  • R 4 is a protecting group for a hydroxy group and R has the meaning as defined above for a compound of formula III.
  • R and R 4 are protecting groups for a hydroxy group, characterized in that R 4 can be split off under reaction conditions that do not result in splitting off the protecting group R 3 , and R has the meaning as defined above for a compound of formula III.
  • a suitable inert solvent e.g., tetrahydrofurane
  • R 3 and R 4 are protecting groups for a hydroxy group, characterized in that R can be split off under reaction conditions that do not result in splitting off the protecting group R 3 .
  • R ⁇ 2 represents aryl lower alkyl, preferably benzyl.
  • the compound of formula XXVI wherein R 3 and R 4 are protecting groups for a hydroxy group, characterized in that R can be split off under reaction conditions that do not result in splitting off the protecting group R 3 and R ⁇ 2 represents aryl lower alkyl, preferably benzyl, is solved in a suitable inert solvent, e.g., tetrahydrofurane, and a suitable reducing agent, e.g. lithium borohydride, solved or suspended in a suitable solvent, e.g. a lower alkanol, is added sequentially at a temperature of between -5 °C and +5 °C, e.g. about 0 C C, and the resulting mixture is stirred for a period of between 12 and 24 hours, e.g. about 16 hours, providing a compound of formula XXVII,
  • the compound of formula XXVll wherein R 3 and R 4 are protecting groups for a hydroxy group, characterized in that R 4 can be split off under reaction conditions that do not result in splitting off the protecting group R 3 .
  • the compound of formula XXVll wherein R 3 and R are protecting groups for a hydroxy group, characterized in that R 4 can be split off under reaction conditions that do not result in splitting off the protecting group R 3 , is transformed into a diene of formula VII wherein R 3 and R,, have the same meaning as for the compound of formula XXVll and X is a leaving group, by transforming the primary hydroxy group in the compound of formula XXVll into a suitable leaving group X, e.g.
  • the compound of formula XXVll can be solved in a suitable solvent, e.g. a di-lower alkyl ether or acetonitrile or a mixture thereof, and treated at a temperature of between -5 °C and +5 °C, e.g. about 0 °C, first with triphenylphosphine and imidazole and secondly at the same temperature with iodine, furnishing a diene of formula VII wherein R 3 and R 4 have the same meaning as in the compound of formula XXVll and X is iodide.
  • a suitable solvent e.g. a di-lower alkyl ether or acetonitrile or a mixture thereof.
  • a ketone of formula II wherein R 2 and R 3 are identical or different protecting groups for a hydroxy group and R is hydrogen can also be obtained by the reaction of the aldehyde of formula IX, wherein R is hydrogen and R 2 and R 3 are identical or different protecting groups for a hydroxy group, with a phosphonate ester of formula LVI
  • Alk' is lower alkyl, preferably methyl, e.g., in the presence of a suitable base, e.g. potassium carbonate together with 18-crown-6, in a suitable solvent, like benzene or toluene together with HMPA, at a temperature between 5 °C and 40 °C, e.g. 20 °C to 25 °C, for about 1 to 5 hours, furnishing an ester of formula LVII
  • R 2 and R 3 are identical or different protecting groups for a hydroxy group, R is hydrogen and Alk' is lower alkyl, preferably methyl,
  • ester of formula LVII under conditions known as such, e.g. by treatment in a mixture of tetrahydrofuran and water with an alkaline base like lithium hydroxide, furnishing the acid of formula LVIII
  • R 2 and R 3 are identical or different protecting groups for a hydroxy group and R 4 is hydrogen
  • R 2 and R 3 are identical or different protecting groups for a hydroxy group and R is hydrogen by reaction with at least two equivalents of methyl lithium, e.g. in tetrahydrofurane, at a temperature between about -90 °C and - 60 °C, e.g. about -80 °C.
  • An aldehyde of formula IX wherein R 4 is hydrogen, and R 2 and R 3 are identical or different protecting groups for a hydroxy group, can be obtained by a reaction sequence, wherein in a first step an aldehyde of formula XXlll, wherein R is a protecting group for a hydroxy group which can be split off under conditions that do not result in the removal of the protecting group R 2 (see below), is reacted with a carbonic acid ester of formula XXIX
  • Ar is aryl, preferably phenyl, which is mono-, di- or trisubstituted by lower alkyl, e.g. 2,6-di-lower alkyl phenyl
  • Ri and R 2 are identical or different protecting groups for a hydroxy group characterized in that the group Ri can be removed under conditions that do not result in the removal of the protecting group R 2 , by adding at a temperature between - 80 °C and - 120 °C, e.g.
  • Ar is aryl, preferably phenyl, which is mono-, di- or trisubstituted by lower alkyl, e.g. 2,6-di-lower alkyl phenyl, wherein Ri, R 2 and R represent different protecting groups for a hydroxy group characterized in that the groups R and R 4 can be removed under conditions that do not result in the removal of the protecting group R 2 .
  • Ri, R 2 and I 4 represent different protecting groups for a hydroxy group characterized in that the groups Ri and R can be removed under conditions that do not result in the removal of the protecting group R 2 , and R 13 is hydrogen, by solving the compound of formula XXX in a suitable solvent, e.g. tetrahydrofuran, and then adding a reduction agent which is capable of transforming an aryl ester into the corresponding primary alkohol, e.g., adding a solution of lithium aluminium hydride in tetrahydrofuran at a temperature between -60 °C and -100 °C, e.g. at about -78 °C.
  • a suitable solvent e.g. tetrahydrofuran
  • R 1 3 is -SO 2 -aryl wherein the aryl radical is unsubstituted or substituted by alkyl, and Hal represent halogen, under reaction conditions known as such, e.g. by adding at about room temperature the reagent XXXII to a solution of the diol of formula XXXI in dichloromethane, obtaining a sulfonate of formula XXXI wherein Ri, R 2 and P represent different protecting groups for a hydroxy group characterized in that the groups Ri and R 4 can be removed under conditions that do not result in the removal of the protecting group R 2 , and Ri 3 is -SO 2 -aryl wherein the aryl radical is unsubstituted or substituted by alkyl.
  • the resulting sulfonate of formula XXXI is reduced, e.g., by treatment with NaBH 4) LiBH 4 , diisobutyl aluminium hydride, LiB(ethyl) 3 H, Zn, tributyl tin hydride or, preferably, LiAIH 4 at a temperatur between about -20 °C and 0 °C, furnishing a triene of formula V,
  • Ri, R 2 and R 4 represent different protecting groups for a hydroxy group characterized in that the groups Ri and R 4 can be removed under conditions that do not result in the removal of the protecting group R 2 , and R 3 represents hydrogen.
  • Suitable reaction conditions for a reduction utilising LiAIH are, for example, described in J. Org. Chem. 1980, 45, 2550 to 2551 or also J. Am. Chem. Soc. 1951, 73, on page 2874 (2nd Example described there).
  • NaBH 4 can, for example, generally be employed in dimethyl sulfoxide or sulfolane at a temperature between 15 °C and 100 °C, e.g. 25 °C or 85 °C, and tributyl tin hydride generally in refluxing 1 ,2-dimethoxyethane (DME) in the presence of sodium iodide.
  • the triene of formula V wherein Ri, R 2 and R represent different protecting groups for a hydroxy group characterized in that the groups Ri and R 4 can be removed under conditions that do not result in the removal of the protecting group R 2 , and R 3 represents hydrogen, can be transferred into a triene of formula V, wherein Ri, R 2 and R 4 have the same meanings and R 3 represents a protecting group for a hydroxy group, which is stable under conditions under which the groups R and R can be removed, e.g., by reaction of the triene of formula V with a reagent of the structure R 3 -triflate in the presence of a base, e.g. tri-lower alkyl amine, in a suitable solvent, e.g. dichloromethane, at a temperature between -60 °C and -100 °C, e.g. about -80 °C.
  • a base e.g. tri-lower alkyl amine
  • a suitable solvent e.g. dichlor
  • the resulting triene of formula V wherein Ri, R 2 , R 3 and R represent different protecting groups for a hydroxy group characterized in that the groups Ri and R 4 can be removed under conditions that do not result in the removal of the protecting groups R 2 and R 3 , is then transferred into a diol of formula V, wherein R ⁇ and R 4 are hydrogen, and R 2 and R 3 are identical or different protecting groups for a hydroxy group, by selectively splitting off the protecting groups Ri and R 4 .
  • the primary alcohol in the diol of formula V wherein Ri and R 4 are hydrogen, and R 2 and R 3 are identical or different protecting groups for a hydroxy group, is selectively oxidised furnishing the aldehyde of formula IX wherein R is hydrogen, and R 2 and R 3 are identical or different protecting groups for a hydroxy group.
  • Suitable oxidising conditions are known as such, e.g., a solution of the diol of formula V in dichloromethane can be treated with 2,2,6,6- tetramethyl-1-piperinyloxy (TEMPO), followed by iodobenzene acetate at a temperature between 10 °C and 30 °C, e.g. about 20 °C.
  • TEMPO 2,2,6,6- tetramethyl-1-piperinyloxy
  • R 15 is lower alkyl, e.g. methyl, which is solved in a suitable solvent, e.g. dichloromethane, and reacted in the presence of catalytic amounts of an acid, e.g. triflic acid, with R ⁇ 6 -2,2,2-trichloroacetimidate at a temperature between 10 °C and 30 °C, e.g. about 20 °C, furnishing a carbonic acid ester of formula XXXIV,
  • Ri is a protecting group for a hydroxy group that can be transformed into a protecting group for a diol, e.g. p-methoxybenzyl, and R 15 is lower alkyl, e.g. methyl.
  • the carbonic acid ester of formula XXXIV wherein Ri is a protecting group for a hydroxy group that can be transformed into a protecting group for a diol, e.g. p- methoxybenzyl, and R ⁇ 5 is lower alkyl, e.g. methyl, is transferred into the amide of formula XXXV,
  • R is a protecting group for a hydroxy group that can be transformed into a protecting group for a diol, e.g. p-methoxybenzyl, by reaction in a suitable solvent like toluene or benzene with N,O-dimethyihydroxylamine hydrochloride in the presence of an equal amount of trimethylaluminium at a temperature between -10 °C and +10 °C, e.g. about 0 °C.
  • the obtained amide of formula XXXV, wherein Ri has the meaning as provided above for a compound of formula XXXIV, is then in a third step subject of a Grignard reaction employing ethylmagnesium bromide under conditions known as such, e.g. a solution of the Grignard reagent in diethylether or tetrahydrofuran is dropped to the solution of the amide of formula XXXV in the same solvent at a temperature of about 0°C in which process the reaction mixture can be punctually warmed or iodine can be added in order to start the reaction.
  • the Grignard reaction is stopped after a period of about 0.5 to 3 hours, e.g. after about 1 hour, providing a ketone of formula XXXVI,
  • ketone of formula XXXVI can be, e.g., added at a temperature between -10 °C and +10 °C, e.g. about 0 °C, to a mixture of dicyclohexylboron chloride and a tri-lower alkyl amine, e.g. triethylamine, in a suitable solvent, e.g. diethylether, and after a period between about 1 and 3 hours, formaldeyhde is added at a temperature between -60 °C and -100 °C, e.g.
  • reaction mixture is warmed to a temperature between -10 °C and +10 °C, e.g. about 0 °C, and a lower alcohol, e.g. methanol, a pH 7 buffer and finally hydrogen peroxide is added.
  • Ri has the meaning as provided above, e.g., the ⁇ -hydroxy ketone of formula XXXVII, can be reacted with the reducing agent sodium triacetoxyborohydride in a suitable solvent, e.g. tetrahydrofuran, at a temperature between -10 °C and +10 °C, e.g. about 0 °C, under reaction conditions known as such.
  • a suitable solvent e.g. tetrahydrofuran
  • the diol of formula XXXVIII, wherein Ri has the meaning as provided above for a compound of formula XXXIV is reacted with tert-butyl-dimethyl-silyl (TBDMS) chloride, triisopropylsilyl (TIPS) chloride or thexyldimethylsilyl (TDS) chloride, preferably TBDMS chloride in the presence of imidazole or another suitable base, providing an alcohol of formula XXXIX,
  • Ri is a protecting group for a hydroxy group that can be transformed into a protecting group for a diol and R 14 is TBDMS, TIPS or TDS.
  • the obtained alcohol is oxidized with a reagent that is capable of transforming the protecting group Ri into a protecting group for a diol, e.g., if R-i represents p- methoxy-benzyl, the reaction can be accomplished with 2,3-dichloro-5,6-dicyano-1 ,4,-benzo- quinone, furnishing a compound of formula XL.
  • a reagent that is capable of transforming the protecting group Ri into a protecting group for a diol, e.g., if R-i represents p- methoxy-benzyl, the reaction can be accomplished with 2,3-dichloro-5,6-dicyano-1 ,4,-benzo- quinone, furnishing a compound of formula XL.
  • R ⁇ 4 is TBDMS, TIPS or TDS and R 16 is a protecting group for a diol, e.g. p-methoxy phenyl.
  • the obtained compound of formula XL is reacted with a reagent that is capable of transforming the protecting group for a diol into a protecting group for a hydroxy group, e.g., if R ⁇ 6 represents p-methoxy phenyl, the reaction can be accomplished with diisobutyl aluminium hydride in tetrahydrofuran under conditions known as such, furnishing an alcohol of formula XLI,
  • R 4 is TBDMS, TIPS or TDS and R is a protecting group for a hydroxy function, e.g. p-methoxy benzyl.
  • the alcohol function in the compound of formula XLI wherein R M is TBDMS, TIPS or TDS and R 4 is a protecting group for a hydroxy function, e.g. p-methoxy benzyl, is oxidized to the corresponding aldehyde.
  • the oxidation of the alcohol function in the compound of formula XLI can be achieved, e.g., by oxidation with Collin's reagent , eerie ammonium nitrate (for reaction conditions see, e.g.
  • R 14 is TBDMS, TIPS or TDS and R 4 is a protecting group for a hydroxy function, e.g. p-methoxy benzyl.
  • R 14 is TBDMS, TIPS or TDS and R is a protecting group for a hydroxy function, e.g. p-methoxy benzyl, e.g., by a Wittig reaction, a Peterson olefination or, in particular, by a Nozaki-Hiyama-Kishi reaction.
  • a suitable inert solvent e.g., tetrahydrofurane
  • the protecting group R u is detached from the diene of formula XLIII under conditions known as such and the obtained free hydroxy function is oxidized to the corresponding aldehyde under conditions as reported for the preparation of the aldehyde XLII by oxidation of the alcohol XLI (see above), furnishing an aldehyde of formula XXlll wherein R 4 is a protecting group for a hydroxy function, e.g. p-methoxy benzyl.
  • the ⁇ -hydroxy ketone of formula XXXVll wherein Ri is a protecting group for a hydroxy group characterized in that the group Ri can be removed under conditions that do not result in the removal of the protecting group R 2 , is selectively oxidized to the corresponding aldehyde of formula XLIV,
  • Ri has the meaning as provided above for a compound of formula XXIX, e.g., by reaction with 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and iodobenzene diacetate, e.g., in dichloromethane at a temperature between - 5°C and + 5 °C, e.g. 0 °C. ln a second step, the obtained aldehyde of formula XLIV, wherein Ri has the meaning as provided above for a compound of formula XXIX, is subjected to a Still-Gennari olefination reaction, the reaction conditions of which are known as such.
  • the olefination can be carried out by solving the reagent of formula XLV
  • Alk represents alkyl, preferably lower alkyl like methyl, in a suitable solvent, e.g. tetrahydrofuran, together with a strong base, e.g. sodium hydride or, preferably, potassium hexamethyldisilazane in the presence of 18-crown-6, and adding at a temperature between - 100°C and - 60 °C, e.g. about -80 °C, the aldehyde of formula XLIV solved in the same solvent, furnishing the alcohol of formula XLVI
  • Ri has the meaning as provided above for a compound of formula XXIX
  • R 2 is hydrogen and Alk represents alkyl, preferably lower alkyl like methyl.
  • a third step the obtained alcohol of formula XLVI is reacted with a reagent introducing a protecting group for a hydroxy group R 2 , which group is stable under conditions which effect cleavage of the protection group Ri, thus furnishing a compound of formula XLVI, wherein Ri has the meaning as provided above for a compound of formula XXIX, R 2 is protecting group for a hydroxy group which group is stable under condition which effect cleavage of the protection group Ri, and Alk represents alkyl, preferably lower alkyl like methyl.
  • R 1 represents p-methoxybenzyl
  • the alcohol of formula XLVI can be reacted with te/f-butyl-dimethyl-si ⁇ yl (TBDMS) chloride in the presence of imidazole or, preferably, TBDMS triflate in the presence of 2,6-lutidine under conditions known as such, thus establishing TBDMS as the protecting group R 2 .
  • TDMMS te/f-butyl-dimethyl-si ⁇ yl
  • the compound of formula XLVI wherein Ri has the meaning as provided above for a compound of formula XXIX, R 2 is protecting group for a hydroxy group which group is stable under condition which effect cleavage of the protection group Ri, and Alk represents alkyl, preferably lower alkyl like methyl, is reacted with a reducing agent which is capable of transforming a carbonic acid ester into the corresponding alcohol under reaction conditions known as such, preferably those reducing agents mentioned herein above, more preferably diisobutylaluminium hydride, furnishing an alcohol of formula XLVIl,
  • Ri has the meaning as provided above for a compound of formula XXIX and R 2 is a protecting group for a hydroxy group which group is stable under conditions which effect cleavage of the protection group Ri.
  • Ri and R 2 have the meanings as provided above for a compound of formula XLVIl and Hal represents halo, preferably bromo.
  • Ar is aryl, preferably phenyl, which is mono-, di- or trisubstituted by lower alkyl, e.g. 2,6-di-lower alkyl phenyl, e.g. by reacting first the compound of formula IL in a suitable solvent, e.g. tetrahydrofuran, in the presence of N,N,N',N',N",N"-hexamethylphosphotriamide with a strong lithium base, preferably lithium diisopropylamide, at a temperature between - 100°C and - 60 °C, e.g.
  • a suitable solvent e.g. tetrahydrofuran
  • R 5 is a protecting group for a hydroxy group
  • R represents R 8 -O-, wherein R 8 represents alkyl
  • R is a protecting group for a hydroxy group
  • R is oxidized to the corresponding acid by reaction with an oxidizing agent, e.g., potassium permanganate in acid, basic or neutral solution (depending on the nature of the protecting group Ri), silver oxide, or, preferably, sodium chlorite, under reaction conditions known as such, providing an carboxylic acid of formula L,
  • an oxidizing agent e.g., potassium permanganate in acid, basic or neutral solution (depending on the nature of the protecting group Ri), silver oxide, or, preferably, sodium chlorite
  • R is a protecting group for a hydroxy group.
  • R is a protecting group for a hydroxy group and R represents R 8 -O-, wherein R 8 represents alkyl, preferably methyl, by reaction with a diazo compound of the formula LI I
  • R 8 represents lower alkyl, in a suitable solvent at a temperature between - 10°C and +30 °C, e.g. about +10 °C.
  • An ester of formula LI wherein R represents methoxy, alternatively can be prepared by reaction of the carbonic acid of formula L with methyl iodide and a suitable base, e.g. potassium carbonate, thus avoiding the hazardous diazomethane.
  • a suitable base e.g. potassium carbonate
  • the hydroxy function in the carboxylic acid ester of formula LI is protected by reaction with a reagent introducing a protecting group which is stable under conditions under which the protecting group Ri can be cleaved, e.g., tert-butyl-dimethyl-silyl (TBDMS) chloride, triisopropylsilyl (TIPS) chloride or thexyldimethylsilyl (TDS) chloride, preferably TBDMS triflate in the presence of 2,6-lutidine or another suitable base, under conditions known as such, furnishing a carboxylic acid ester of formula LI II
  • R is a protecting group for a hydroxy group
  • R 5 is a protecting group for a hydroxy group which is stable under conditions under which the protecting group Ri can be cleaved
  • R represents R 8 -0-, wherein R 8 represents alkyl, preferably methyl.
  • the protecting group Ri is splitt off under conditions under which the protecting group R 5 remains untouched.
  • Ri represents p-methoxybenzyl (PMB) and R 5 represents TBS or another oxidatively stable protecting group
  • a suitable oxidation reagent which is known to splitt of a PMB group, e.g. 2,3-dichloro-5,6-dicyano-1,4,-benzoquinone (DDQ).
  • PMB p-methoxybenzyl
  • R 5 represents TBS or another oxidatively stable protecting group
  • DDQ 2,3-dichloro-5,6-dicyano-1,4,-benzoquinone
  • the person skilled in the art is aware of numerous further combinations of two protecting groups for a hydroxy function in which the one group can be cleaved whereas the second group remains in place. All such combinations are incldued in the present invention.
  • the fourth step furnishes an alcohol of formula LIV
  • R 5 is a protecting group for a hydroxy group and R represents R 8 -O-, wherein R 8 represents alkyl, preferably methyl.
  • the obtained alcohol of formula LIV is oxidized to the aldehyde of formula III wherein R 5 is a protecting group for a hydroxy group and R- represents R 8 -0- by reaction with a suitable oxidizing agent, e.g., by oxidation with Collin's reagent , eerie ammonium nitrate (for reaction conditions see, e.g. Trahanovsky et al, J. Chem. Soc.
  • DMSO in conjunction with a further suitable reagents, like acetic anhydride, oxalyl chloride, or, especially, a S0 3 -pyridine complex in the presence of a tertiary amine as defined above, preferably triethylamine, or, especially, with N-methyl-morpholineoxide in the presence of a suitable Ru complex, e.g. tetrapropylammonium perruthenate (for suitable reaction conditions see, e.g., Ley et ai, Synthesis 1994, 639).
  • a suitable reagents like acetic anhydride, oxalyl chloride, or, especially, a S0 3 -pyridine complex in the presence of a tertiary amine as defined above, preferably triethylamine, or, especially, with N-methyl-morpholineoxide in the presence of a suitable Ru complex, e.g. tetrapropylammonium perruthenate (
  • radicals R 2 , R 3 , R» and R 5 have the meanings as provided for a compound of formula IV above, comprise a diastereoselective reduction followed by a lactonization reaction or a lactonization reaction followed by a diastereoselective reduction of a tetraene of formula IV
  • the tetraene of formula IV is first lactonised, e.g., by treatment with a mild acid, such as acetic acid, furnishing a ketone of formula LIX
  • the present invention also relates to a ketone of formula LIX, wherein R 2 , R 3 and R 5 are identical or different protecting groups for a hydroxy group, and R 4 is hydrogen or H 2 NC(0)-.
  • the reaction mixture is treated sequentially and under temperature control (ca 0 °C, cooling bath at -20 °C) with EtOH/THF 1 :1 v/v (520 mL) over a period of 25 min, pH 7 phosphate buffer (520 mL) over a period of 15 min and 35% aqueous hydrogen peroxide (250 L) over a period of 20 min.
  • EtOH/THF 1 :1 v/v 520 mL
  • pH 7 phosphate buffer 520 mL
  • 35% aqueous hydrogen peroxide 250 L
  • the resulting solution is stirred successively at 0 °C for 1 h and at 23 °C for 14 h before being extracted twice with hexane (1500 mL and 1000 mL).
  • the organic extracts are washed with Na 2 S 2 0 3 (1000 mL and 600 mL) and pH 7 phosphate buffer (600 mL), combined, dried (MgSO 4 ) and concentrated in vacuo.
  • the residue is dissolved in a mixture of CH 2 CI 2 (1000 mL) and H 2 0 (600 mL) and the pH of the water layer of the resultant two-phase mixture is increased from 4.1 to 11.2 by dropwise addition monitored with a pH-meter over a period of 1 h of 1 N NaOH (110 mL). After, the pH of the aqueous layer remains stable at 11.2 for 15 min, the layers are separated.
  • the organic layers are washed with aqu. sat.
  • Stage 1.4 ( ?)-3-r(2R3S.4S)-3-(tert-Butvl-dimethvl-silanvloxv)-5-hvdroxv-2.4-dimethvl- pentanoyl]-4-isopropyl-5,5-diphenyl-oxazolidin-2-one
  • Acetic acid 150 g, 2.50 mol is added to a turbid emulsion of crude compound from stage 2.1 (117.2 g) in a mixture of THF/CH 3 OH/H 2 0 5:5:1 v/v/v (300 mL) at 23 °C.
  • the resulting solution is heated at 50 °C for 5 h.
  • the reaction mixture is quenched with H 2 0 (800 mL) and extracted with TBME (2 x 500 mL).
  • the organic extracts are washed with aqu. sat. NaHC0 3 (400 mL) and aqu. sat.
  • the organic extracts are washed with aqu. sat. NaHCO 3 (50 mL), and H 2 0 (2 x 50 mL), combined, dried (MgSO 4 ) and concentrated in vacuo.
  • Stage 6.1 (R)-3-f(2R3S.4S)-3-(tert-Butvl-dimethvl-silanvloxv)-2.4-dimethyl-5-triethvl- silanyIoxy-pentanoyl]-4-isopropyl-5,5-diphenyl-oxazolidin-2-one
  • a solution of the product of stage 1.4 (6.75 g, 12.5 mmol), imidazole (0.96 g, 14.1 mmol), and DMAP (145 mg, 1.2 mmol) in DMF (11.0 mL) at 0 °C under an atmosphere of Ar is treated dropwise over a period of 5 min with TESCI (1.92 g, 12.7 mmol).
  • a 2.0 M solution of LiBH 4 (6.55 mL, 13.10 mmol) in THF is added to a solution of the crude product of stage 6.1 (5.36 g, 8.19 mmol) in 130 mL of diethylether and 234 ⁇ L (13.02 mmol) of water at 0 °C over a period of 10 min. The mixture is allowed to warm to RT over night. Another 73 ⁇ L (4.06 mmol) of water and 2.05 mL (4.09 mmol) of a 2 M LiBH 4 solution are added at 23 °C.
  • reaction mixture is diluted with hexane (300 mL) and poured into sat. aqu. NH 4 CI (500 mL) at 0 °C.
  • the pH during the addition is carefully controlled and maintained at a value between 5 and 7 by addition of additional 1 N HCI (33 mL).
  • the layers are then separated and the aqu. layer is extracted with hexane (2 x 300 mL).
  • the organic extracts are washed with sat. aqu. NaCl (2 x 300 mL), combined, dried (MgS0 ) and concentrated in vacuo.
  • Stage 7.4 (Z)-(2R,3S.4S)-2.4-Dimethvl-3-triethvlsilanvloxv-octa-5.7-dienal
  • a solution of the product of stage 7.3 (5.123 g, 15.0 mmol) in THF (14 mL) at -30 °C is treated under an atmosphere of Ar dropwise with a 1.5 molar solution of DIBALH in toluene (10.5 mL, 15.8 mmol). After stirring at -30 °C for 40 min, the reaction is quenched with MeOH (3 mL). Thereafter, sat. aqu. potassium sodium tartrate (200 mL) and hexane (200 mL) are added.
  • the layers are separated and the aqu. layer is extracted with hexane (2 x 100 mL).
  • the organic extracts are washed with sat. aqu. NaHC0 3 (2 x 100 mL) and sat. aqu. NaCl (100 mL), combined, dried (MgS0 4 ) and concentrated in vacuo.
  • Stage 7.5 (R)-3-f(Z)-(2R,3S.4S.55,6S)-3-Hvdroxy-2,4,6-trimethvl-5-triethvlsilanvloxv-deca- 7,9-dienoyl]-4-isopropyl-5,5-diphenyl-oxazolidin-2-one
  • a solution of (R)-4-isopropyl-5,5-diphenyl-3-propionyl-oxazolidin-2-one (961 mg, 2.85 mmol) in CH 2 CI 2 (3.0 mL) at 0 °C under an atmosphere of Ar is treated sequentially with n-Bu 2 BOTf (1 M in CH 2 CI 2 , 2.70 mL, 2.70 mmol) and triethylamine (0.50 mL, 3.47 mmol).
  • Stage 7.6 (R)-3-r(Z)-(2R3S,4R5S,6S)-3-(tert-Butvl-dimethvl-silanvloxv)-2.4,6-trimethvl-5- triethylsilanyIoxy-deca-7,9-dienoyl]-4-isopropyl-5,5-diphenyl-oxazolidin-2-one
  • a solution of the product of stage 7.5 (1.06 g, 1.71 mmol) and 2,6-lutidine (0.515 mL, 4.44 mmol) in CH 2 CI 2 (8 mL) at -20 °C under an atmosphere of Ar is treated dropwise with TBDMSOTf (0.915 mL, 4.00 mmol).
  • the resulting reaction mixture is allowed to warm-up at 0 °C within 30 min and stirred for an additional 2 h and 30 min.
  • TBME (25 mL) and 1N HCI (15 mL) are added sequentially and the layers are separated.
  • the aqu. layer is extracted with TBME (25 mL).
  • the organic layers are washed with 1N HCI (15 mL), sat. aqu. NaHCO 3 (15 mL) and sat. aqu. NaCl (15 mL), combined, dried over MgS0 4 and concentrated in vacuo.
  • reaction solution is stirred successively at - 78 °C for 15 min and at 0 °C for 30 min.
  • Phosphate buffer pH 7, 6.0 mL
  • MeOH 9.0 mL
  • MeOH/35% H 2 0 2 (6:1 v/v, 7.0 mL) are then added sequentially at 0 °C.
  • the resulting two phase mixture is treated with 40% aqu. Na 2 S 2 0 3 (6.0 mL).
  • the volatiles are removed in vacuo and the residual aqu. phase is diluted with H 2 0 (20 mL) and extracted with AcOEt (2 x 40 mL).
  • the combined organic layers are washed with sat. aqu.
  • reaction mixture is diluted with hexane (30 mL) and poured into sat. aqu. NH 4 CI (50 mL) at 0 °C.
  • the pH during the addition is carefully controlled and maintained at a value between 5 and 7 by addition of additional 1 N HCI (3.3 mL).
  • the layers are separated and the aqu. layer is extracted with hexane (2 x 30 mL).
  • the organic extracts are washed with sat. aqu. NaCl (2 x 30 mL), combined, dried (MgS0 4 ) and concentrated in vacuo.
  • stage 9.3 (Z)-(2S,3S.4S)-2,4-Dimethvl-3-triethylsilanvloxv-octa-5,7-dien-1 -ol
  • a 2.0 M solution of LiBH 4 (6.55 mL, 13.10 mmol) in THF is added to the product of stage 9.2 (4.60 g, 8.19 mmol) in 130 mL of diethylether and 234 ⁇ L (13.02 mmol) of water at 0 °C over a period of 10 min.
  • Example 10 (3Z.11Z)-(5S,6S.7S,8R9S.13S.14R15S)-8.14-Bis-(fert-butyl-dimethyl- silanyloxy)-5.7.9.11.13.15-hexamethyl-6.16-bis-triethylsilanyloxy-hexadeca-1.3.11-triene
  • a dried reactor (50 mL) equipped with a magnetic stirring bar and under an atmosphere of argon is charged sequentially with n-hexane (3.7 mL) and a solution of f-BuLi in pentane (3.50 L, 6.02 mmol, 1.7 M). The resulting solution is cooled to -78 °C.
  • a solution of the product of Example 7 (1.59 g, 2.80 mmol) in Et 2 0 (16.8 mL) is added within 5 min so that the internal temperature of the reaction mixture does not exceed -75 °C. At the end of the addition, the reaction mixture is stirred at -78 °C for no longer than 10 min.
  • the reaction mixture is stirred at 23 °C over night.
  • the heterogeneous reaction mixture (ca 68 mL) is filtrated over a pad of cellflock before being extracted with heptane (2 x 50 mL).
  • the heptane fractions are back-extracted with a 1:1 v/v mixture of aqu. sat. NaCl and water (2 x 30 mL) before being combined and dried over MgS0 4 .
  • the heptane fraction is concentrated in vacuo at 40 °C to 12 L.
  • To the resulting turbid brown solution containing a dark-brownish precipitate ethanolamine (245 mg, 4.00 mmol, 1.1 eq. per eq.
  • Example 11 Carbamic acid (6Z.11ZH1S,2R3R4S,8S,9S.10S)-3,9-bis-(te/f-butyl-dimethyl- silanyloxy)-2.4, 6.8.10-pentamethyl-1-( (Z)-(S)-1 -methyl-penta-2,4-dienyl)-13-oxo-tetradeca- 6.11-dienyl ester
  • Stage 11.1 (3Z, 11 Z)-(5S,6S,7S,8R,9S, 13S, 14R,15S)-8, 14-Bis-(ferf-butyl-dimethyl-silanyl- oxyJ- ⁇ J. ⁇ .II.IS.I ⁇ -hexamethyl- ⁇ .ie-bis-triethylsilanyloxy-hexadeca-I.S.II-triene
  • Stage 11.2 (5Z,13Z)-(2R.3R4S,8S.9R,10R11S.12S)-3.9-Bis-(ten'-butvl-dimethvl-silanvl- oxy)-11-hydroxy-2,4,6,8,10,12-hexamethyl-hexadeca-5,13,15-trienal
  • a solution of the product of stage 11.1 (20.0 g, 33.5 mmol) in CH 2 CI 2 (100 mL) at 0 °C under an atmosphere of argon is treated sequentially with TEMPO (1.05 g, 6.7 mmol) and iodobenzene diacetate (32.4 g, 100.9 mmol).
  • the resulting orange suspension is stirred at RT for 3 h after which a 3:1 v/v mixture of 5% aqu. Na 2 S 2 0 3 and 30% aqu. Na 2 S 2 0 3 (400 mL) is added dropwise followed by TBME (400 mL). The layers are separated and the aqu. layer is extracted with TBME (150 mL). The organic extracts are washed with 8% aqu. NaHC03 (200 mL) and aqu. sat. NaCl (300 mL), combined, dried over MgSO 4 and concentrated in vacuo.
  • Stage 11.3 (3Z,8Z, 16Z)-(5S,6S,7S, 11 S, 12R, 13R, 14S, 15S)-6, 12-Bis-(ferf-butyl-dimethyl- silanyloxy)-14-hydroxy-5,7,9,11 , 13,15-hexamethyl-nonadeca-3,8,16,18-tetraen-2-one
  • a suspension of anhydrous micronized K 2 C0 3 (1.70 g, 12.3 mmol) and 18-crown-6 (6.55 g, 24.8 mmol) in a 45:5 v/v mixture of toluene and HMPA (27.3 mL) is stirred for 2 h and 45 min at ambient temperature before being cooled at -15 °C and treated dropwise within 10 min with a solution of the product of stage 11.2 (1.23 g, 2.07 mmol) and (2-oxo-propyl)- phosphonic acid bis- (2,2,2-trifluoro
  • Example 12 (8Z.13Z.21Z -(2R3S.4S.5S.10S.11S.12S.16S.17R18S.19S.20S)-3.11.17-Tris- (terf-butyl-dimethyl-silanyloxy)-19-carbamoyloxy-5-hvdroxy-2.4.10.12.14.16.18,20- octamethyl-7-oxo-tetracosa-8, 13.21.23-tetraenoic acid methoxy-methyl-amide
  • reaction mixture is stirred at -78 °C for 20 h before being allowed to warm up to 0 °C and is quenched by the addition of pH 7 phosphate buffer (20 mL).
  • the aqueous layer is extracted with TBME (2 x 30 mL).
  • the organic extracts are washed with sat. aqu. NaHC0 3 (30 mL) and brine (30 mL), combined, dried (MgS0 4 ) and concentrated in vacuo.
  • Example 13 (R)-4-lsopropyl-5,5-diphenyl-3-f(8Z.13Z.21Z)-(2R3S.4S.5S.10S.11S.12S, 16S.17R18S.19S.20S)-3.11.17-tris-fterf-butyl-dimethyl-silanyloxy)-19-carbamoyloxy-5- hvdroxy-2.4.10.12.14.16.18.20-octamethyl-7-oxo-tetracosa-8.13.21.23-tetraenovn- oxazolidin-2-one
  • the aqueous layer is extracted with TBME (2 x 30 mL).
  • the organic extracts are washed with sat. aqu. NaHC0 3 (30 mL) and brine (30 mL), combined, dried (MgS0 4 ) and concentrated in vacuo.
  • the residue is purified by flash-chromatography (100 g of Si0 2 , 95:5 heptane/AcOEt) to give the desired aldol product as a colorless foam.
  • Stage 14.1 Methyl (S)-3-(p-MethoxybenzyIoxy)-2-methyipropionate
  • methyl (S)-3-hydroxy-2-methylpropionate and p-methoxybenzyltrichloroacetimidate (18.9 g, 66.9 mmol, 1.2 eq.) in Et2 ⁇ (400 mL) at 0°C
  • a solution of triflic acid in Et2 ⁇ 1.5 mL of a 0.45 M solution, 0.67 mmol
  • Stage 14.2 (S)- ⁇ /-Methoxy- ⁇ /,2-dimethyl-3-(p-Methoxybenzyloxy)propanamide
  • To a stirred mixture of 7.03 g (29.53 mmol, 1.0 eq.) of the ester of stage 14.1 and N,0- dimethyl hydroxylamine hydrochloride (4.36 g, 44.68 mmol, 1.5 eq.) in THF (400 mL) at -30°C is added isoPrMgCI (44.7 mL of a 2M solution in THF, 89.37 mmol, 3.0 eq.) dropwise, maintaining the reaction temperature below -20 °C at all times. After 45 min at this temperature, aqu.
  • Stage 14.3 (S)-1-(p-Methoxybenzyloxy)-2-methylpentan-3-one (13)
  • EtMgCI (11.9 L of a 2M solution in Et2 ⁇ , 23.7 mmol, 2.0 eq.
  • the reaction mixture is stirred for 2.5 h, allowing the temperature to reach 5°C. It is then carefully quenched with aqu. NH4CI (100 mL). The aqu. layer is extracted with Et2 ⁇ (4 x 100 mL).
  • Stage 14.4 (2S, 4S)-1 -Hydroxy-5-(p-methoxybenzyloxy)-2,4-dimethylpentan-3-one
  • Dicyclohexylboron chloride (6.17 mL, 28.15 mmol, 1.3 eq) is dissolved in Et2 ⁇ (80 mL), and the resulting mixture is cooled to 0°C before the addition of Et ⁇ (4.83 mL, 34.6 mmol, 1.6 eq.).
  • the ethyl ketone of stage 14.3 (5.11 g, 21.6 mmol, 1.0 eq.) is added via cannula as an Et2 ⁇ solution (15 mL) and the mixture is stirred at 0°C for 2 hours.
  • a freshly prepared formaldehyde solution is added to the reaction mixture via cannula. After 1 hour at -78°C the reaction mixture is allowed to warm to 0°C before the addition of MeOH (80 mL) and pH 7 buffer (80 mL). Hydrogen peroxide (30 mL, 30% aqueous) is added dropwise at 0°C. After 1 h at RT, the mixture is extracted with dichloromethane (3 x 200 mL). The combined extracts are dried (MgSO4) and concentrated in vacuo.
  • Stage 14.5 (2S, 3R 4S)-5-(p-Methoxybenzyloxy)-2,4-dimethylpentane-1,3-diol
  • Sodium triacetoxyborohydride (6.35 g, 29.98 mmol, 4.0 eq.) is carefully dried in vacuo before the addition of THF (100 mL).
  • the slurry is cooled to 0°C and the ⁇ -hydroxyketone of stage 14.3 (1.99 g, 7.49 mmol, 1.0 eq) dissolved in THF (50 mL) is added via cannula.
  • Acetic acid (5 mL) is added dropwise and the mixture is stirred at 0°C for 30 min and then at RT for 20 h.
  • Stage 14.9 (Z)-(2S, 3S, 4S)-3-(p-Methoxybenzyloxy)-2,4-dimethyl-octa-5,7-dien-1-ol
  • CSA (306 mg, 1.32 mmol)
  • the reaction is partitioned between NaHC ⁇ 3 (20 mL) and CH2CI2 (3 x 50 mL).
  • Stage 16.2 (3Z, 5S, 6S, 7R 8S, 9R, 11Z, 13S, 14R 15S)-14-(f-Butyldimethylsilyloxy)-6,16- bis-(p-methoxybenzyloxy)-9-(hydroxymethyl)-5,7,11 ,13,15-pentamethyl-hexadeca-1 ,3,11- trien-8-ol
  • Stage 16.3 (3Z, 5S, 6S, 7R, 8S, 9R 11Z, 13S, 14R 15S)-14-(f-Butyldimethylsilyloxy)-6,16- bis-(p-methoxybenzyloxy)-9-[(2,4,6-trimethylphenyl)sulfoxymethyl]-5,7,11,13,15- pentamethyl-hexadeca-1 ,3,11 -trien-8-ol
  • Et3N (683 ⁇ L, 4.85 mmol)
  • 2,4,6-trimethylphenyl sulfonylchloride (318 mg, 1.45 mmol).
  • Stage 16.4 (3Z, 5S, 6S, 7S, 8R, 9S, 11Z, 13S, 14R 15S)-14-(f-Butyldimethylsilyloxy)-6,16- bis-(p-methoxybenzyloxy)-5,7,9,11,13,15-hexamethyl-hexadeca-1,3,11-trien-8-ol
  • UAIH4 5.83 mL of a 1M/THF solution, 5.83 mmol
  • Oxalylchloride (distilled, 29 ml, 0.33 mmol, 1.5 eq) is dissolved in dichloromethane (1 ml) and cooled to -78°C.
  • DMSO 47 ml, 0.66 mmol, 3 eq
  • the semi crude alcohol from stage 17.4 (max 0.219 mmol) is added in dichloromethane (2 ml) via cannula and the reaction mixture is stirred for 45 min at -78°C.
  • Triethylamine (214 ml, 1.53 mmol, 7 eq) is added and the mixture is stirred for 20 min at -78°C before being allowed to warm up slowly to RT.
  • Stage 17.2 Methyl (2R, 3S, 4S)-2,4-dimethyl-3-hydroxy-5-(4-methoxybenzyloxy)pentanoate
  • the acid of stage 17.1 (max 1.866 mmol) is dissolved in DMF (5 ml).
  • Potassium carbonate (313 mg, 2.26 mmol, 1.2 eq) is added, followed by iodomethane (176 mL, 2.83 mmol, 1.5 eq).
  • the reaction mixture is diluted with water (20 mL), extracted with EtOAc (5 x 10 mL).
  • EtOAc 5 x 10 mL
  • the combined organic extracts are dried (Na2S04) and concentrated in vacuo.
  • the crude mixture is purified by flash chromatography (silica gel, 10% EtOAc in hexane) yielding the desired ester as a white solid with a mp of 56 °C.
  • Example 18 (3Z. 5S. 6S. 7S. 8Z. 11S. 12R 13S. 14S. 15S. 16Z)-6. 12 -Bis-(t- butyldimethylsilyloxy)-14-hydroxy-5. 7, 9 .11 .13 ,15 -hexamethylnonadeca-3 .8 ,16 ,18 - tetraen-2-one
  • 18-crown-6 (2.44 g, 9.26 mmol, 12 eq) and K2CO3 (640 mg, 4.631 mmol, 6 eq, ground and dry heated) are stirred in toluene (4 ml) and HMPA (0.4 ml) at RT for 3 h before cooling to - 15°C.
  • the Still-Gennari reagent of stage 18.2 (932 mg, 3.087 mmol, 4 eq) and the aldehyde of Example 16 are dissolved in toluene (4 mL) and HMPA (0.4 mL) and added to the reaction mixture via cannula. The mixture is stirred for 5 h with slowly warming to 4°C before being left over night in the fridge.
  • Stage 18.1 Methylphosphonic acid bis(2,2,2-trifluoroethyl) ester
  • a solution of trifluoroethanol (5.48 mL, 75.2 mmol, 2 eq) and triethylamine (11.6 mL, 83.1 mmol, 2.21 eq) in THF (125 mL) is cooled to 10°C.
  • a solution of methanephosphonic dichloride (5.00 g, 37.6 mmol, 1 eq) in THF (20 mL) is added via a dropping funnel.
  • a precipitate forms, the mixture is stirred at RT for 2 h, the precipitate is filtered off, washed with THF (60 mL) and the filtrate is concentrated in vacuo.
  • Stage 18.2 (2-Oxo-propyl)phosphonic acid bis(2,2,2-trifluoroethyl) ester
  • a solution of the product of stage 18.1 (8.54 g, 32.8 mmol) and acetyl chloride (2.8 mL, 39.4 mmol, 1.2 eq) in THF (10 mL) is added slowly via cannula to LiHMDS (69 mL of a 1M solution in THF, 69 mmol, 2.1 eq) at -98°C. After addition the mixture is stirred for 1 h before being quenched 3N HCI (20 mL) and allowed to warm up to RT. The aqu.
  • Example 19 (3Z. 5S. 6S. 7S. 8Z. 11S, 12R 13S, 14S, 15S. 16Z)- 6, 12 -Bis-(f- butyldimethylsilyloxy) -14-carbamoyloxy-5. 7 .9 .11 .13 .15 -hexamethylnonadeca-3, 8. 16. 18 -tetraen-2-one
  • Example 20 Methyl (2R 3S. 4S. 5S. 8Z. 10S, 11S, 12S, 13Z. 16S, 17R 18S, 19S. 20S. 21Z.)-3,7.11-tris(t-butyldimethylsilyloxy)-19-carbamoyloxy-5-hvdroxy-2. 4. 10. 12. 14, 16. 18. 20-octamethyl-7-oxotetracosa-8. 13. 21. 23-tetraenoate
  • reaction mixture After stirring at -78°C for 6 h, the reaction mixture is stored for 17 h in the freezer at -78°C. It is then quenched by the addition of pH7 buffer (3 mL). After extraction with ethyl acetate (4 x 5 mL), washing with NaHC03 and brine, drying (Na2S04) and evaporation of most of the solvent, the reaction mixture is purified by preparative TLC (eluent syste : 33% EtOAc / hexane) to give the desired product as a white foam; Rf: 0.5 (33% EtOAc / hexane); 13 C NMR (100 MHz, CDCI3) ⁇ c 200.8, 176.2, 157.0, 152.1, 133.6, 132.7, 132.1, 130.3, 129.7, 125.4, 117.9, 80.5, 78.6, 77.0, 73.7,
  • the aldol from Example 20 (13 mg, 0.0134 mmol) is dissolved in THF (0.5 mL). Water (0.5 mL) is added, followed by AcOH (0.5 mL). The reaction mixture is stirred at RT for 3 days, before being partitioned between aqu. NaHC03 (10 mL) and EtOAc (5 mL). The aqu. layer is re-extracted with EtOAc (5 x 5 mL). The combined organic extracts are dried (Na2S04), and concentrated under vacuum. The crude product is purified by flash chromatography (Silica gel, 20% EtOAc / Hexane) to give the desired product as a white solid.
  • the keto-lactone from from Example 21 (11 mg, 0.012 mmol) is dissolved in toluene (2 mL) and the solution is cooled down to -78°C.
  • K-Selectride (1M in THF, 0.024 mmol, 24 ⁇ L, 2 eq) is added and the reaction mixture is stirred at -78°C for 3 h, before being quenched with one drop of AcOH and allowed to warm up to RT.
  • pH7 buffer (2 mL) is added, followed by 1 drop of H2O2 (30% solution), and the reaction mixture is stirred at RT for 45 min. After dilution with pH7 buffer (5 mL), the aqu.
  • Stage 24 Methyl (2R.3S,4R)-3-triethylsilyloxy-2,4-dimethyl-5-oxo-pentanoate
  • Methyl (2R3S,4R)-3-triethylsilyloxy-2,4-dimethyl-5-oxo-pentanoate may be prepared according to example 17 wherein TESOTf is used instead of TBSOTf in stage 17.3.
  • Stage 24.1 2R. 3S. 4S-3-(triethylsilanyloxy)-5-(4-methoxybenzyloxy)-2.4-dimethylpentanoic acid methoxy-methyl amide.
  • the reaction mixture is stirred for 30 - 60 minutes at 0 - 5°C and treated with sodium hydrogen sulphate (120 g of a 10% solution).
  • the phases are separated and the aqueous phase is re-extracted with toluene (63 g).
  • the combined organic phases are washed twice with water (2 x 120 g) and the solvent removed in vacuum at 40°C to give 37 g, 110% of the crude silyl ether as an oil.
  • This crude material is chromatographed in two portions of 18 g over silica gel (150 g) eluting initially with heptane/ethyl acetate 15/1 followed by ethyl acetate to gives the purified product as an oil.
  • Stage 24.3 (2R 3S. 4S)- 3-triethylsilyloxy-5-(4-methoxybenzyloxyV2,4-dimethyl-pentanal Weinreb amide of stage 24.2 (1.68 g, 3.82 mmol) is dissolved in toluene (10 mL) and cooled to -30°C. Red-AI (3.5M in toluene, 1.64 mL, 5.73 mmol, 1.5 eq.) is added via a dropping funnel; the latter is further rinsed with toluene (5 mL), which is added to the reaction mixture.
  • Red-AI 3.5M in toluene, 1.64 mL, 5.73 mmol, 1.5 eq.
  • Stage 24.6 Methyl (2R3S,4S)-3-triethylsilyloxy-2,4-dimethyl-5-hvdroxy-pentanoate Ester of stage 24.5 (30 mg, 0.073 mmol) is dissolved in DCM (2 mL). pH 7 buffer (0.2 mL) is added, and the solution is cooled to 0°C. DDQ (20 mg, 0.088 mmol, 1.2 eq.) is added slowly, and the reaction mixture is stirred for 1 h at 0°C. pH 7 buffer (20 mL) is added to the mixture, and it is extracted with AcOEt (5 x 10 mL). The combined organic extracts are dried over Na2S ⁇ 4 and concentrated under vacuum. Purification by flash chromatography on silica gel
  • a solution of the ketone of Example 19 (176 mg, 0.259 mg) is dissolved in Et20 (1 mL) and cooled to 0°C.
  • c-Hex2BCI (1M in hexanes, 0.777 mL, 0.777 mmol, 3 eq.) is added, followed immediately by Et3N (0.119 mL, 0.855 mmol, 3.3 eq.), and the reaction mixture is stirred at 0°C for 40 min, before being cooled to -78°C, and stirred at that temperature for 10 min.
  • a solution of 6.7g (10.52mMol) of the acid of stage 24 is dissolved in 80mL of diethyl ether and cooled to an internal temperature of -20°C. Maintaining the internal temperature between -20°C and -10°C 23.1 mL of a 5% solution of methyl lithium in diethyl ether is added slowly within a period of 30 min. The reaction mixture is warmed to 0°C and stirred at that temperature overnight. After this time the pH of the reaction mixture is adjusted to between 3 and 4 with a 10% aqu. solution of citric acid. The organic phase is separated, washed with water and dried with sodium sulphate. The suspension is filtered and the solvent removed in vacuum to deliver the crude product as colourless oil.
  • Stage 26.1 (2Z,7Z,15Z)-(4S,6S,10S,12R, 14S)-5(S),11(R)-Bis-(.tert.-butyl-dimethyl- silanyloxy)-13(S)-hydroxy-4,6,8,10,12,14-hexamethyl-octadeca-2,7,15,17-tetraenoic acid
  • Example 27 (3Z. 5S. 6S. 7R 8S. 9R. 11Z, 13S. 14R 15S)-14-(t-Butyldimethylsilyloxy)-6.16- bis-(o-methoxybenzyloxy)-9-(hvdroxymethyl)-5,7,11 ,13,15-pentamethyl-hexadeca-1 , 3,11- trien-8-ol
  • reaction mixture is stirred at - 78°C for 1 hr and then allowed to gradually warm to 0°C over 1 hr.
  • the reaction is quenched by the careful addition of potassium sodium tartrate (3 mL) and stirred vigorously at RT. After 30 min, the layers are separated and the aqueous layer is extracted with Et2 ⁇ (3 x 5 mL). The combined organics are dried (Na2S ⁇ 4) and concentrated in vacuo. Flash chromatography (30% on
  • Stage 27.3 (4-Methoxy-2.6-Dimethylphenyl) (2S. 3S. 4S, 5S, 6S, 7Z)-2-lT2Z, 4S, 5R. 6S)-5- (t-butyldimethylsilyloxy)-7-(p-methoxybenzyloxy)-2,4,6-trimethyl-hept-2-enyll-3-hvdroxy-5-(p- methoxybenzyloxy)-4,6-dimethyl-deca-7.9-dienoate
  • Example 28 Methyl (2R. 3S. 4S. 5S, 8Z. 10S, 11S, 12S, 13Z. 16S, 17R 18S. 19S. 20S. 21Z,)-3,7,11-tris(t-butyldimethylsilyloxy)-19-carbamoyloxy-5-hydroxy-2. 4, 10. 12. 14. 16. 18. 20-octamethyl-7-oxotetracosa-8, 13. 21. 23-tetraenoate.
  • the flasks containing the aldehyde is rinsed twice with 0.4 mL Et2 ⁇ , and these washings are added to the reaction mixture. After stirring at - 78°C for 2 h, the reaction mixture is quenched by the addition of pH7 buffer (3 mL), and allowed to warm up to 0°C. After extraction with Et2 ⁇ (2 x 5 mL), the combined organic extracts are diluted with MeCN (20 mL) and H2O (5 mL) and put straight on top of a column packed with reverse phase silica (eluent : MeCN/H2 ⁇ , 98:2). MeCN/ ⁇ O is passed through the column to get rid of the by-products derived from the excess aldehyde and cHex2BCI.

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Abstract

The invention relates to a process for preparing discodermolide, for preparing intermediates for the manufacture of discodermolide and discodermolide analogues and to the intermediates obtained during the process. Wherein the process proceeds via a tetraene of formula (IV).

Description

Synthesis of Discodermolide
The invention relates to a process for preparing discodermolide, for preparing intermediates for the manufacture of discodermolide and discodermolide analogues and to the intermediates obtained during the process.
Figure imgf000002_0001
(+)-DISCODERMOLlDE
(+)-Discodermolide is a poly etide natural product that was isolated from extracts of the marine sponge Discodermolide dissoluta by researchers at the Harbor Branch Oceano- graphic Institution [S.P. Gunasekera et al., J. Org. Chem. 1990;55:4912-15 (published erratum appears in J. Org. Chem. 1991:56:1346)]. Discodermolide lacks obvious structural resemblance to paclitaxel, yet it shares with paclitaxel (the active substance in the drug Taxol®) the ability to stabilize microtuhu)es. Pacϊitaxel has proven to be useful in treating some types of cancer in clinical practice. Discodermolide binds to tubulin competitively with paclitaxel and was shown to have utility against hyperproliferative disorders (see, e.g., WO 97/20835). Future development of discodermolide or structurally related analogues is hindered by the lack of a natural source that could provide greater amounts of the compound, since naturally occurring discodermolide is scarce and harvesting the producing organism presents logistical problems. Accordingly, there is a need for efficient processes for the manufacture of discodermolide and analogues thereof and for novel intermediates for such processes of manufacture which processes and intermediates enable the manufacture of commercially acceptable quantities of discodermolide and structurally related analogues.
The present invention relates to a process for preparing a lactone of formula I
Figure imgf000003_0001
wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group and R4 is H2NC(0)-, in which process in a first step a triene of formula V
Figure imgf000003_0002
wherein
Ri, R2, R3 and R4 are protecting groups for a hydroxy group, characterized in that R^ and R4 can be split off under reaction conditions that do not result in cleavage of any of the protecting groups R2 or R3> is prepared by the reaction of a vinyl iodide of formula VI,
Figure imgf000003_0003
wherein R1 and R2 are different protecting groups for a hydroxy group, characterized in that Ri can be split off under reaction conditions that do not result in the cleavage of the protecting group R2, with a diene of formula VII,
Figure imgf000004_0001
wherein R3 and R4 are different protecting groups for a hydroxy group and X is a leaving group, characterized in that R4 can be split off under reaction conditions that do not result in the cleavage of the protecting group R3,
in a second step the protecting groups Ri and R4 are split off to provide a compound of formula V, wherein Ri and R4 are hydrogen, and R2 and R3 are identical or different protecting groups for a hydroxy group,
in a third step the only primary hydroxy group in the compound of formula V is selectively oxidized to provide an aldehyde of formula IX
Figure imgf000004_0002
wherein R4 is hydrogen, and R2 and R3 are identical or different protecting groups for a hydroxy group,
in a fourth step the aldehyde of formula IX is reacted with a phosphonate ester of formula X OCH CF,
P— OCH2CF3
O
(X)
furnishing a ketone of formula II
Figure imgf000005_0001
wherein R2 and R are identical or different protecting groups for a hydroxy group and R4 is hydrogen,
optionally, in a fifth step such ketone of formula 11 is reacted with Cl3C(0)NCO in the presence of neutral Al203 to provide a ketone of formula II, wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is H2NC(0)-,
in a sixth step an aldol coupling reaction is conducted of said ketone of formula II with an aldehyde of formula III
Figure imgf000005_0002
wherein
Rs is a protecting group for a hydroxy group, and
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or (c) a substructure of formula Ilia
Figure imgf000006_0001
wherein R9 represents alkyl or aryl, Rι0 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the aldehyde of formula III via the nitrogen atom, to provide a tetraene of formula IV
Figure imgf000006_0002
wherein
R2, R3 and R5 are identical or different protecting groups for a hydroxy group,
R4 is hydrogen or H2NC(0)-,
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia wherein Rg represents alkyl or aryl, R10 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom, wherein the tetraene of formula IV wherein R is H2NC(0)- subsequently is the subject of a diastereoselective reduction followed by a lactonization reaction, or of a lactonization reaction followed by a diastereoselective reduction, to provide the lactone of formula I, wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group, or
wherein the tetraene of formula IV wherein R is hydrogen, subsequently is the subject of a lactonization reaction followed by a reaction installing the carbamate and a diastereoselective reduction, to provide the lactone of formula I, wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group and R4 is H2NC(0)-.
The obtained compounds of formula I, wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group and R4 is H2NC(0)-, can be transformed into a compound of formula I, wherein R2, R3 and R5 are hydrogen and R is H2NC(O)- ((+)- discodermolide), by cleavage of the protecting groups R2, R3 and R5 under suitable conditions known as such, e.g. by treatment with hydrogenchloride in a lower alkanol if R2, R3 and R5 represent tri-Iower alkyl silyl radicals.
The total synthesis of discodermolides was already described in the literature, e.g. by Amos B. Smith III. et al in J. Am. Chem. Soc. 1995, 117, 12011-12012. A key feature of the present convergent synthesis described herein is the use of a C-i-Cs subunit (the aldehyde of formula III) and a C6-C24 subunit (the ketone of formula II) for the creation of the discodermolide carbon scaffold. It has a number of advantage over the methods described in the literature, especially in terms of suitability of large scale production of (+)-discodermolide and analogues thereof. For example, the hydroboration on the substrates of formula XII proceeds in good yields and with >95% diastereoselectivity. This approach avoids the expensive Roche ester, which is employed frequently in methods described in the state of the art. Furthermore, all the intermediates to the lactones of Example 1 and 2 are crystalline, which is also the case for the lactone of Example 1. Crystallinity of the intermediates in the early stage of the total synthesis constitutes a major advantage as it much simplifies the purifications and avoids costly chromatographies. Additionally, the access to the common intermediates of Example 1 and 2 is shorter and/or more practical as well as higher yielding than the synthesis of common precursors described in the prior art. A further advantage is that the chiral auxiliary, e.g. ( ?)-4-isopropyl-5,5-diphenylpropionyloxazolidin-2-one, can be efficiently recycled by precipitation and filtration during the lactonization reaction. A common building block that can be employed in the present approach is the diol of formula XXXVIII, wherein Ri represents p-methoxybenzyl (see below), which is also crystalline and can be obtained from the commercially available starting material of formula XXXIII in a 5-step sequence which can be performed with minimal chromatographic purification.
Within the present disclosure, the general definitions used hereinbefore and hereinafter preferably have the following meaning, if not indicated otherwise:
The term "protecting groups for a hydroxy group" as used herein refers to acid labile, fluoride labile and / or oxidatively labile protecting groups for a hydroxy group, which groups are known as such. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products.The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter. Preferred protecting groups are silyl ethers which are acid labile or fluoride labile like tert-butyl-dimethyl-silyl (TBDMS) ether, triethylsilyl (TES) ether, triisopropylsilyl (TIPS) ether, diethylisopropylsilyl (DEIPS) ether, isopropyldimethylsilyl (IPDMS) ether or thexyldimethylsilyl (TDS) ether; esters which are acid labile like pivaloate ester; substituted benzyl ethers which are oxidatively labile like 3,4-dimethoxybenzyl (DMPM) ether or p-methoxybenzyl (PMB) ether; substituted ethylethers which are acid labile like 1- ethoxyethyl (EE) ether, 1-(2-(trimethylsi!yl)ethoxy)ethyl (SEE) ether, 1-methyl-1-methoxyethyl (MIP-OR) ether, 1 -methyl- 1-benzyloxyethyl (MBE) ether or 2-trimethylsilylethyl ether; substituted methyl ethers which are acid labile or fluoride labile like 2-methoxyethoxymethyl (MEM) ether, methoxymethyl (MOM) ether, benzyloxy ethyl (BOM) ether, p-methoxybenzyl- oxymethyl (PMBM) ether, ferf-butoxymethyl ether, tetrahydropyranyl (THP) ether, siloxymethyl ether or trimethylsilyl)ethoxymethyl (SEM) ether; and trityl ether.
The prefix "lower" means that the respective moiety preferably has up to and including a maximum of 7 carbon atoms, more preferably up to 4 carbon atoms.
Alkyl is preferably lower alkyl which can be linear or branched and is especially methyl, ethyl; n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or, preferably, methyl or ferf-butyl. Aryl is an aromatic radical which is bound to the molecule via a bond located at an aromatic ring carbon atom of the radical. In a preferred embodiment, aryl is an aromatic radical having 6 to 14 carbon atoms and denotes especially monocyclic aryl, in particular phenyl, or bicyclic aryl, in particular naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, and is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from amino, halogen, lower alkyl, hydroxy, etherified or lower alkoxy, nitro, cyano, carboxy, lower alkanoyl, benzoyl and carbamoyl. Aryl is more preferably phenyl.
Any reference to other documents or publications within this application means that the respective document or publication is included by reference into the present disclosure.
The protecting groups Rt and R4 can be identical or different to each other and can be split off under reaction conditions under which the protecting groups R2 and R3 remain in place.
In one embodiment of the invention, Ri and R4 together with the oxygen atom to which they are attached independently of each other form a TES ether; a trityl ether; an acid labile substituted ethyl ether, in particular SEE ether, MIP-OR ether or MBE ether; an oxidatively labile substituted benzyl ether, in particular PMB ether or DMPM ether; or an acid labile substituted methyl ether, in particular a THP ether.
In another embodiment of the invention, R2 and R3 each represent a PMB radical and Ri and R4 together with the oxygen atom to which they are attached independently of each other form a silyl ether which is acid labile or fluoride labile, especially a TBDMS ether, TIPS ether, DEIPS ether, IPDMS ether or TDS ether; a substituted ethyl ether which is acid labile, especially EE ether or 2-trimethylsilylethyl ether; a substituted methyl ether, especially MEM ether, MOM ether, BOM ether, PMBM ether, ferf-butoxymethyl ether, siloxymethyl ether or SEM ether; or an acid labile ester, especially a pivaloate ester.
In a preferred embodiment of the invention, Ri and R4 each represent a TES radical and R2 and R3 together with the oxygen atom to which they are attached are preferably employed as silyl ethers which are acid labile or fluoride labile, especially TBDMS ether, TIPS ether, DEIPS ether, IPDMS ether and TDS ether; esters which are acid labile, especially pivaloate ester; benzyl ethers which are oxidatively labile, especially DMPM ether or PMB ether; substituted ethylethers which are acid labile or fluoride labile, especially 1-ethoxyethyl ether and 2-trimethylsilylethyl ether; substituted methyl ethers which are acid labile or fluoride labile, especially MEM ether, MOM ether, BOM ether, PMBM ether, te/ -butoxymethyl ether, siloxymethyl ether or SEM ether.
R5 is preferably a silyl ether, in particular, selected from TES, TBDMS, TIPS, DEIPS, IPDMS and TDS ether; a pivaloate ester; a substituted benzyl ether, in particular, selected from PMB and DMPM ether; a substituted ethyl ether, in particular, selected from EE, SEE, MIP-OR, MBE and 2-trimethylsilylethyl ether; or a substituted methyl ether, in particular, selected from MEM, MOM, BOM, PMBM, terf-butoxymethyl, THP, siloxymethyl and SEM ether. In one preferred embodiment of the invention, R5 is TBDMS.
Rg is preferably methyl, isopropyl, benzyl or phenyl.
R10 and Rn are preferably both phenyl.
R is preferably (a) R6-0-N(R7)- wherein R6 and R7 are independently of each other lower alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5, (b) R8-O-, wherein R8 represents lower alkyl, or (c) a substructure of formula Ilia wherein R9 represents lower alkyl or C6-CMaryl, Rw and Rn represent independently of each other hydrogen, lower alkyl or C6- Cι4aryl, and which substructure is bound to the rest of the molecula via the nitrogen atom. More preferably, R is R6-0-N(R7)- wherein R6 and R7 are independently of each other lower alkyl or (c) a substructure of formula Ilia wherein R9 represents lower alkyl or phenyl, Rι0 and Rn represent independently of each other hydrogen, lower alkyl or phenyl.
X is preferably a halogen selected from chloride, bromide and iodide. Most preferably, X is iodide.
The present invention relates furthermore to a process for preparing a triene of formula V wherein
R- and R4 are hydrogen, and
R2 and R3 are identical or different protecting groups for a hydroxy group, in which process a vinyl iodide of formula VI, wherein Ri and R2 are different protecting groups for a hydroxy group, characterized in that
Ri can be split off under reaction conditions that do not result in splitting off the protecting group R2, is reacted with a diene of formula VII, wherein R3 and R4 are different protecting groups for a hydroxy group, characterized in that
R4 can be split off under reaction conditions that do not result in splitting off the protecting group R3, and wherein afterwards, the protecting groups Ri and R4 are split off simultaneously or sequentially.
Furthermore, the present invention relates to a vinyl iodide of formula VI wherein Ri and R2 are different protecting groups for a hydroxy group, characterized in that R can be split off under reaction conditions that do not result in splitting off the protecting group R2, especially a vinyl iodide of formula VI wherein Ri is triethylsilyl and R2 is tert-butyl-dimethyl-silyl, and the salts thereof, if applicable.
Furthermore, the present invention relates to a diene of formula VII, wherein R3 and R4 are different protecting groups for a hydroxy group, characterized in that R4 can be split off under reaction conditions that do not result in splitting off the protecting group R3, especially a diene of formula VII wherein R4 is triethylsilyl and R3 is tert-butyl-dimetbyl-silyJ, and the salts thereof, if applicable.
Additionally, the present invention provides a process for preparing a tetraene of formula IV wherein
R2, R3 and R5 are identical or different protecting groups for a hydroxy group,
R4 is hydrogen or H2NC(0)-,
R represents
(a) R6-0-JM(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia wherein R9 represents alkyl or aryl, R10 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom, in which process a ketone of formula II wherein R2 and R3 are identical or different protecting groups for a hydroxy group,
R4 is hydrogen or H2NC(0)-, is reacted with an aldehyde of formula III wherein
R5 is a protecting group for a hydroxy group, and
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) Rs-O-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia wherein R9 represents alkyl or aryl, Rι0 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the aldehyde of formula III via the nitrogen atom, and wherein, optionally, afterwards, the groups R, R2 R3 and R5 are split off simultaneously or sequentially.
Furthermore, the present invention relates to a tetraene of formula IV wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group, R.1 is hydrogen or H2NC(0)-, R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia wherein R9 represents alkyl or aryl, Rι0 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom, and the salts thereof, if applicable.
Another aspect of the present invention is a process for preparing a lactone of formula I, wherein R2, R3 and R5 are hydrogen and R4 is H2NC(0)- ((+)-discodermolide), wherein a ketone of formula II wherein R2 and R3 are identical or different protecting groups for a hydroxy group and Rt is hydrogen or H2NC(0)-, is reacted with an aldehyde of formula III wherein R5 is a protecting group for a hydroxy group, and R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia wherein R9 represents alkyl or aryl, Rio and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the aldehyde of formula III via the nitrogen atom, to provide a tetraene of formula IV wherein
R2, R3 and R5 are identical or different protecting groups for a hydroxy group,
R4 is hydrogen or H2NC(O)-,
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia wherein R9 represents alkyl or aryl, R10 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom, wherein the tetraene of formula IV wherein φ is H2NC(0)- subsequently is the subject of a diastereoselective reduction followed by a lactonization reaction, or of a lactonization reaction followed by a diastereoselective reduction, to provide the lactone of formula I, wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group, or wherein the tetraene of formula IV wherein R is H and, if R4 is hydrogen, subsequently is the subject of a lactonization reaction followed by a reaction installing the carbamate and a diastereoselective reduction, to provide the lactone of formula I, wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group and R4 is H2NC(O)-, and wherein finally the protecting groups are split off from the compound of formula I to provide (+)-discodermoIide.
A further aspect of the present invention is a process for preparing a lactone of formula IB
Figure imgf000014_0001
wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group and R is H2NC(0)-, wherein in a first step the keto group in a tetraene of formula IV wherein
R2, R3 and R5 are identical or different protecting groups for a hydroxy group,
R4 is hydrogen or H2NC(0)-, and
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) a substructure of formula Ilia wherein R9 represents alkyl or aryl, R10 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom, is reduced by a reducing agent capable of transferring an α,β-unsaturated ketone into an α,β-unsaturated alcohol, furnishing a diol of formula LV
Figure imgf000014_0002
wherein
R2, R3 and R5 are identical or different protecting groups for a hydroxy group,
R4 is hydrogen or H2NC(O)-, and
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) a substructure of formula Ilia wherein R9 represents alkyl or aryl, Rι0 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom; in a second step the obtained diol of formula LV is subject of a δ-lactonisation reaction; and in the final third step all protecting groups are removed.
In such process, preferably a reducing agent capable is used that provides selectively a diol of formula (7S)-LV as the major product,
Figure imgf000015_0001
wherein the radicals and symbols have the meanings as provided for a compound of formula LV above. Lactonisation of a compound of formula (7S)-LV provides a compound of formula I, wherein the radicals and symbols have the meanings as provided for a compound of formula LV above.
Furthermore, the present invention pertains to a ketone of formula II
wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is hydrogen or H2NC(O)-.
The present invention furthermore provides the. δ-valerolacton of the formula VIII
Figure imgf000016_0002
General process conditions
All process steps described herein can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralisiing agents, for example ion exchangers, typically cation exchangers, for example in the H+ form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from -100°C to about 190°C, preferably from about -80°C to about 150°C, for example at -80 to -60°C, at room temperature, at - 20 to 40°C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen. The solvents from which those can be selected which are suitable for the reaction in question include for example water, esters, typically lower alkyl-lower alkanoates, e.g diethyl acetate, ethers, typically aliphatic ethers, e.g. diethylether, or cyclic ethers, e.g. tetrahydrofuran, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically methanol, ethanol or 1- or 2-propanol, nitrites, typically acetonitrile, halogenated hydrocarbons, typically dichloromethane, acid amides, typically dimethylformamide, bases, typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids, typically lower alkanecarboxylic acids, e.g. acetic acid, carboxylic acid anhydrides, typically lower alkane acid anhydrides, e.g. acetic anhydride, cyclic, linear, or branched hydrocarbons, typically cyclohexane, he- xane, or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the process. Such solvent mixtures may also be used in processing, for example through chromatography or distribution.
Salts of the compounds mentioned herein with a salt-forming group may be prepared in a manner known perse. Acid addition salts may thus be obtained by treatment with an acid or with a suitable anion exchange reagent. Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
Stereoisomeric mixtures, e.g. mixtures of diastereomers, can be separated into their corresponding isomers in a manner known per se by means of suitable separation methods. Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of one of the starting compounds, the intermediates or in a compound of formula I itself. Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
Preparation of a triene of formula V
The triene of formula V wherein Ri, R2) R3 and R are identical or different protecting groups for a hydroxy group, characterized in that Ri and f^t can be split off under reaction conditions that do not result in splitting off the protecting group R2 and R3, can be prepared by a Suzuki coupling reaction of a vinyl iodide of formula VI, wherein Ri and R2 are different protecting groups for a hydroxy group, characterized in that Ri can be split off under reaction conditions that do not result in splitting off the protecting group R2, with a compound of formula VII, wherein R3 and R4 are different protecting groups for a hydroxy group, characterized in that R4 can be split off under reaction conditions that do not result in splitting off the protecting group R3, which compound is first reacted with ferf-butyl lithium in an inert solvent, e.g. an alkane like pentane, hexane, cyclohexane or heptane or an ether like diethylether or tetrahydrofurane, or a mixture of such solvents, at a temperature between -70 °C and - 85 °C, preferably between -75 °C and -78 °C, than under same condition the obtained reaction product is reacted with a reagent suitable to transform the obtained intermediate into a borane, e.g. B-methoxy-9-borabicyclo[3.3.1]nonane (B-methoxy-9-BBN). The obtained borane is than reacted with the compound of formula VII solved in a suitable solvent, e.g. dimethylformamide or toluene, in the presence of caesium carbonate or sodium carbonate and a palladium (II) catalyst, e.g. Pd(dppf)CI2 CH2CI2 or Pd(AcO)2 together with P(ortho- to!yl)3. Suzuki coupling reactions are known as such, see e.g. Hegedus, Organische Synthesen mit Uebergangsmetallen, S. 83f, Weinheim, VCH, 1995.
From the triene of formula V the protecting groups Ri and R can be split off by reactions known in the art providing a diol of formula V, wherein Ri and R4 are hydrogen, and R2 and R3 are identical or different protecting groups for a hydroxy group. The protection of hydroxy groups by protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981 , in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie" (Methods of organic chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine" (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974. For example, if Ri and R4 each represent a TES radical and R and R3 together with the oxygen atom to which they are attached are TBDMS ethers, cleavage of the TES ethers without cleaving the TBDMS ethers can be achieved by hydrolysis of the compound of formula V in a suitable solvent like tetrahydrofurane or a lower alkanol or, preferably, a mixture thereof, at a temperature between 0 °C and 50 °C, for example, room temperature, by addition of water and chloroacetic acid.
Preparation of an aldehyde of formula IX
An aldehyde of formula IX wherein R is hydrogen and R2 and R3 are identical or different protecting groups for a hydroxy group can be obtained by oxidation of a diol of formula V wherein Ri and R are hydrogen, and R2 and R3 are identical or different protecting groups for a hydroxy group by sequentielly reacting the diol of formula V, with 2,2,6,6-tetramethyl- piperidine 1-oxyl (TEMPO) and iodobenzene diacetate, e.g., in dichloromethane at a temperature between - 5°C and + 5 °C, e.g. 0 °C.
Preparation of a ketone of formula II
A ketone of formula II wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is hydrogen can be obtained by the reaction of the aldehyde of formula IX, wherein R4 is hydrogen and R2 and R3 are identical or different protecting groups for a hydroxy group, with a phosphonate ester of formula X in the presence of a suitable base, e.g. potassium carbonate together with 18-crown-6, in a suitable solvent, like benzene or toluene together with HMPA, at a temperature between 5 °C and 40 °C, e.g. 20 °C to 25 °C, for 1 to 5 hours.
If desired, such ketone of formula II wherein R4 is hydrogen can be reacted in CH2CI2 with CI3CNCO at a temperature between 5 °C and 40 °C, e.g. 20 °C to 25 °C, for 2 to 6 hours to provide a ketone of formula II, wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is CI3CN(H)C(0)-. By hydrolysis in the presence of neutral Al203 the obtained ketone of formula II, wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is CI3CN(H)C(0)-, can be further transferred into a ketone of formula II, wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R is H2NC(O)-.
Preparation of a tetraene of formula IV A ketone of formula IV wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group, R4 is hydrogen or H2NC(0)-, R represents (a) R6-0-N(R7)- wherein Re and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3,
4 or 5, (b) Ra-O-, wherein R8 represents alkyl, or (c) a substructure of formula Ilia wherein R9 represents alkyl or aryl, Rι0 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom, can be obtained by an aldol coupling reaction of the ketone of formula II wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is hydrogen or H2NC(0)-, respectively, with an aldehyde of formula 111 wherein R5 is a protecting group for a hydroxy group, and R has the meaning as given above for the tetraene of formula IV. For such purpose the ketone of formula IV is solved in an inert solvent at a temperature between -
5 °C and + 5 °C, e.g. about 0 °C, and dicyclohexylborochloride (cHex2BCI) is added followed by a suitable base, e.g. a tertiary amine, the solution is stirred for about 15 to 60 minutes, the reaction is cooled to a temperature between -85 °C and - 70 °C, e.g. -78 °C, and a solution of the aldehyde in a di-lower alkyl ether or tetrahydrofurane is added dropwise and the reaction mixture is stirred at the same temperature for 12 to 36 hours, e.g. 20 hours or 24 hours. Suitable as tertiary amine is especially ammonia substituted by three radicals selected independently of one another from alkyl, especially lower alkyl, such as methyl or ethyl, and cycloalkyl having from 3 to 7 carbon atoms, especially cyclohexyl, for example N,N-dimethyl-N-cyclohexylamine, N-ethyl-N,N-diisopropylamine or triethylamine, or, furthermore, also pyridine, N-methylmorpholine or 4-dimethylaminopyridine.
Preparation of the starting materials
It is one of the advantageous aspects the present invention that the preparation of the compounds of formula III, VI and VII can be based on the common precursor of formula XIII and/or the common precursor of formula XVI.
Preparation of the common precursor of formula Xlll
A diol of formula XIII,
Figure imgf000021_0001
wherein R has the meaning as defined above for a compound of formula III, can be obtained by reacting in a first step a compound of formula XI,
Figure imgf000021_0002
wherein R has the meaning as defined above for a compound of formula III, with a mixture of a suitable base, e.g. a tertiary amine as defined above, and a di-lower alkyl boro triflate in a suitable solvent, in particular dichloromethane, at a temperature between -70 °C and -85 °C, e.g. about -78 °C, and adding at the same temperature to the obtained intermediate over a period of between 15 and 45 minutes, e.g. 30 minutes, a solution of methacrolein in the same or a different solvent, and stirring thereafter for about 30 minutes to 90 minutes, e.g. 60 minutes, the mixture at a temperature between -5 °C and +5 °C, e.g. about 0 °C; in order to obtain a compound of formula XII,
Figure imgf000021_0003
wherein R has the meaning as defined above for a compound of formula III, and transforming the compound of formula Xll in a second step via a hydroboration reaction into the diol of formula XIII as defined above, e.g. by adding the compound of formula Xll in a suitable inert solvent, e.g. tetrahydrofurane, dropwise to a solution of a suitable borane, e.g. thexyl borane, in a suitable inert solvent, e.g. also tetrahydrofurane, at a temperature between -5 °C and +5 °C, e.g. about 0 °C, over a period of between 20 and 60 minutes, e.g. about 40 minutes.
Preparation of the common precursor of formula XVI
In a first step, a R2-triflate, wherein R2 is a protecting group for a hydroxy group, is added dropwise over a period of between 20 and 60 minutes, e.g. about 35 minutes, at a temperature between -5 °C and +5 °C, e.g. about 0 °C, to a solution of the compound of formula XIII, wherein R has the meaning as defined above for a compound of formula III, in a suitable inert solvent, e.g. dichloromethane, and 2,6-lutidine, furnishing a compound of formula XIV,
Figure imgf000022_0001
wherein R has the meaning as defined above for a compound of formula Iff and R2 is a protecting group for a hydroxy group.
In a second step, a solution of the compound of formula XIV, wherein R has the meaning as defined above for a compound of formula III and R2 is a protecting group for a hydroxy group, in a lower alkanol, e.g. methanol, is further reacted with dichloroacetic acid at a temperature between -5 °C and +5 °C, e.g. about 0 °C, for a period of between 90 and 120 minutes, e.g. about 100 minutes, furnishing a compound of formula XV,
Figure imgf000022_0002
wherein R2 is a protecting group for a hydroxy group and R has the meaning as defined above for a compound of formula III.
Finally, the lacton of formula XVI,
Figure imgf000023_0001
wherein R2 is a protecting group for a hydroxy group, can be obtained by the reaction of a compound of formula XV, wherein R2 is a protecting group for a hydroxy group and R has the meaning as defined above for a compound of formula III, with a catalytic amount of a potassium alcoholate, e.g. potassium tert-butanolate, in a suitable solvent, e.g. tetrahydrofurane, at a temperature between about -10 °C and + 10 °C, e.g. 0 °C.
Preparation of compounds of formula III
As mentioned above, the common precursor of formula XV can be employed to furnish different fragments of the final compound of formula I. When the common precursor of formula XV is employed to furnish the aldehyde of formula III, the radical R5 in the aldehyde of formula III is identical to the radical R2 in the compound of formula XV.
The aldehyde of formula III wherein Rs is a protecting group for a hydroxy group, and R has the meaning as given above, can be obtained in one step by oxidation of the compound of formula XV wherein R2 is a protecting group for a hydroxy group and R has the meaning as defined above for a compound of formula III. The oxidation of the alcohol function in the compound of formula XV to the aldehyde function in aldehyde of formula III can be achieved, e.g., by oxidation with Collin's reagent , eerie ammonium nitrate (for reaction conditions see, e.g. Trahanovsky et al, J. Chem. Soc. 5777, 1965), N-methyl-morpholineoxide in the presence of a suitable Ru complex (for reaction conditions see, e.g. Sharpless et al, Tetrahedron Lett. 2503, 1976), and in particular, with DMSO in conjunction with a further suitable reagents, like acetic anhydride, oxalyl chloride, or, especially, a S03-pyridine complex in the presence of a tertiary amine as defined above, preferably triethylamine. The latter reaction is preferably carried out in a suitable inert solvent, e.g. dichloromethane, for a period of between 2 and 4 hours, e.g. about 3 hours, at a temperature between -5 °C and +5 °C, e.g. about 0 °C.
Preparation of compounds of formula VI
In a first step, a lactone of formula XVI, wherein R2 is a protecting group for a hydroxy group, solved in a suitable inert solvent, e.g., tetrahydrofurane, is treated at a temperature between 15 °C and 35 °C, e.g. about 20 °C, with N.O-dimethylhydroxylamine hydrochloride and the resulting suspension is cooled to a temperature of between -15 °C and -25 °C, e.g. about -20 °C. A solution of a suitable Grignard reagent, e.g. isopropylmagnesium chloride, in a suitable inert solvent, e.g., tetrahydrofurane, is added dropwise over a period of between 15 and 45 minutes, e.g. about 30 minutes, and stirred at the same temperature for a period of between 5 and 30 minutes, e.g. about 15 minutes, providing a hydroxamic acid of formula XVII
Figure imgf000024_0001
wherein R2 is a protecting group for a hydroxy group.
In a second step, the hydroxamic acid of formula XVII, wherein R2 is a protecting group for a hydroxy group, solved in a suitable inert solvent, e.g., dimethylformamide, is reacted at a temperature between -5 °C and +5 °C, e.g. about 0 °C, for a period of between 2 and 4 hours, e.g. about 3 hours, in the presence of imidazole and dimethylaminopyridine with R Y. wherein R is is a protecting group for a hydroxy group characterized in that Ri can be split off under reaction conditions that do not result in splitting off the protecting group R2, and Y is a suitable leaving group, e.g. a halogenide like chloride or bromide, furnishing a hydroxamic acid of formula XVIII,
Figure imgf000025_0001
(XVIII)
wherein Ri and R2 are protecting groups for a hydroxy group as defined above for a compound of formula VI.
In a third step, the hydroxamic acid of formula XVIII, wherein Ri and R2 are protecting groups for a hydroxy group as defined above for a compound of formula VI, solved in a suitable inert solvent, e.g. benzene or toluene, is reduced by reaction with Red-AI™ in toluene, at a temperature between -30 °C and -50 °C, e.g. about -40 °C, for a period of between 60 and 90 minutes, e.g. about 75 minutes, and quenching the reaction by addition of aqueous potassium sodium tartrate at the same temperature, providing an aldehyde of formula XIX,
Figure imgf000025_0002
wherein Ri and R2 are protecting groups for a hydroxy group as defined above for a compound of formula VI.
Finally, the aldehyde of formula XIX is subject of a Wittig reaction. For such purpose, to a solution of ethyltriphenylphosphonium iodide in a suitable inert solvent, e.g. tetrahydrofurane, at a temperature of between 15 °C and 30 °C, e.g. about 20 °C, a solution of sodium hexamethyldisilazan in a suitable inert solvent, e.g. tetrahydrofurane, is added dropwise and the obtained mixture is stirred for a period of between 15 and 45 minutes, e.g. about 30 minutes, after which period a soultion of iodide in the same solvent is added at a temperature of between -70 "C and -85 °C, e.g. about -78 °C, over a period of between 60 and 90 minutes, e.g. about 75 minutes. After further 15 to 45 minutes at the same temperature, the aldehyde of formula XIX wherein Ri and R2 are protecting groups for a hydroxy group as defined above for a compound of formula VI, is added in order to obtain the compound of formula VI as defined above.
Preparation of dienes of formula VII
As mentioned above, the common precursor of formula XVI can be employed to furnish different fragments of the final compound of formula I. When the common precursor of formula XVI is employed to furnish the diene of formula VII, the radical R in the diene of formula VII is identical to the radical R2 in the compound of formula XVI.
In the first step, a lactone of formula XVI, wherein R2 is a protecting group for a hydroxy group, solved in a suitable inert solvent, e.g., tetrahydrofurane, is treated at a temperature between 15 °C and 35 °C, e.g. about 20 °C, with N.O-dimethylhydroxylamine hydrochloride and the resulting suspension is cooled to a temperature of between -15 °C and -25 °C, e.g. about -20 °C. A solution of a suitable Grignard reagent, e.g. isopropylmagnesium chloride, in a suitable inert solvent, e.g., tetrahydrofurane, is added dropwise over a period of between 15 and 45 minutes, e.g. about 30 minutes, and stirred at the same temperature for a period of between 5 and 30 minutes, e.g. about 15 minutes, providing a hydroxamic acid of formula XX
Figure imgf000026_0001
wherein R4 is a protecting group for a hydroxy group.
In the second step, the alcohol function in the hydroxamic acid of formula XX, wherein Rφ is a protecting group for a hydroxy group, is oxidized to the corresponding aldehyde. The oxidation of the alcohol function in the compound of formula XX an be achieved, e.g., by oxidation with Collin's reagent , eerie ammonium nitrate (for reaction conditions see, e.g. Trahanovsky et al, J. Chem. Soc. 5777, 1965), N-methyl-morpholineoxide in the presence of a suitable Ru complex (for reaction conditions see, e.g. Sharpless et al, Tetrahedron Lett. 2503, 1976), and in particular, with DMSO in conjunction with a further suitable reagents, like acetic anhydride, oxalyl chloride, or, especially, a SO3-pyridine complex in the presence of a tertiary amine as defined above, preferably triethylamine. The latter reaction is preferably carried out in a suitable inert solvent, e.g. dichloromethane, for a period of between 2 and 4 hours, e.g. about 3 hours, at a temperature between -5 °C and +5 °C, e.g. about 0 °C, providing a hydroxamic acid of formula XXI
Figure imgf000027_0001
wherein R4 is a protecting group for a hydroxy group.
In the third step, the hydroxamic acid of formula XXI, wherein R4 is a protecting group for a hydroxy group, is transformed to the diene of formula XXII,
Figure imgf000027_0002
wherein R4 is a protecting group for a hydroxy group, e.g., by a Wittig reaction, a Peterson olefination or, in particular, by a Nozaki-Hiyama-Kishi reaction. For the latter reaction, the hydroxamic acid of formula XXI solved in a suitable inert solvent, e.g., tetrahydrofurane, is reacted at a temperature between -5 °C and +5 °C, e.g. about 0 °C, with CrCI2 and (1-halo- allyl)-tri-lower alkyl silane, e.g. (l-bromo-allyl)-trimethylsilane, for a period of between 2 and 6 hours, e.g., 4 hours, and, afterwards, the obtained intermediate solved in a suitable inert solvent, e.g., tetrahydrofurane, is added to a suspension of a strong base, e.g. potassium hydride, solved in a suitable inert solvent, e.g., tetrahydrofurane, at a temperature between -5 °C and +5 °C, e.g. about 0 °C.
In the fourth step, the hydroxamic acid of formula XXII, wherein R4 is a protecting group for a hydroxy group, is transformed into the aldehyde of formula XXlll by reduction with a suitable reagent, e.g. by solving the hydroxamic acid of formula XXII in a suitable inert solvent, e.g. benzene or toluene, and reaction with Red-AI™ in toluene, at a temperature between -30 °C and -50 °C, e.g. about -40 °C, for a period of between 60 and 90 minutes, e.g. about 75 minutes, and quenching the reaction by addition of aqueous potassium sodium tartrate at the same temperature, providing the aldehyde of formula XXlll,
Figure imgf000028_0001
(XXlll)
wherein R is a protecting group for a hydroxy group. Alternatively, the hydroxamic acid of formula XXII can be solved in a suitable inert solvent, e.g., tetrahydrofurane, and be treated at a temperature between -25 °C and -35 °C, e.g. about -30 °C, with diisobutylaluminium hydride furnishing also said aldehyde of formula XXlll.
In the fifth step, the aldehyde of formula XXlll, wherein R is a protecting group for a hydroxy group, is reacted with a compound of formula XI, wherein R has the meaning as defined above for a compound of formula III, which compound of formula XI is first reacted with a mixture of a suitable base, e.g. a tertiary amine as defined above, and a di-lower alkyl boro triflate in a suitable solvent, in particular dichloromethane, both at a temperature between -70 °C and -85 °C, e.g. about -78 °C, providing a compound of formula XXIV,
Figure imgf000029_0001
wherein R4 is a protecting group for a hydroxy group and R has the meaning as defined above for a compound of formula III.
In the sixth step, to a solution of the compound of formula XXIV, wherein R4 is a protecting group for a hydroxy group and R has the meaning as defined above for a compound of formula III, and 2,6-lutidine in a suitable inert solvent, e.g. dichloromethane, a R3-triflate, wherein R3 is a protecting group for a hydroxy group, characterized in that R4 can be split off under reaction conditions that do not result in splitting off the protecting group R3, is added at a temperature of between -25 °C and -15 °C, e.g. about -20 °C, furnishing a compound of formula XXV,
Figure imgf000029_0002
wherein R and R4 are protecting groups for a hydroxy group, characterized in that R4 can be split off under reaction conditions that do not result in splitting off the protecting group R3, and R has the meaning as defined above for a compound of formula III.
In the seventh step, the solution of the compound of formula XXV, wherein R3 and R4 are protecting groups for a hydroxy group, characterized in that R4 can be split off under reaction conditions that do not result in splitting off the protecting group R3, and R has the meaning as defined above for a compound of formula III, in a suitable inert solvent, e.g., tetrahydrofurane, is added dropwise at a temperature between -5 °C and +5 DC, e.g. about 0 °C, to a solution of an aryl lower alkyl mercaptan (Rι2-S-H), in a suitable inert solvent, e.g., tetrahydrofurane, which mercaptan is treated before at a temperature between -5 °C and +5 °C, e.g. about 0 °C, over a period of between 10 and 20 minutes, e.g. about 15 minutes, dropwise with a solution of n-butyl lithium in an inert solvent, e.g. hexane, to give a compound of formula XXVI,
Figure imgf000030_0001
wherein R3 and R4 are protecting groups for a hydroxy group, characterized in that R can be split off under reaction conditions that do not result in splitting off the protecting group R3. and Rι2 represents aryl lower alkyl, preferably benzyl.
In the eighth step, the compound of formula XXVI, wherein R3 and R4 are protecting groups for a hydroxy group, characterized in that R can be split off under reaction conditions that do not result in splitting off the protecting group R3 and Rι2 represents aryl lower alkyl, preferably benzyl, is solved in a suitable inert solvent, e.g., tetrahydrofurane, and a suitable reducing agent, e.g. lithium borohydride, solved or suspended in a suitable solvent, e.g. a lower alkanol, is added sequentially at a temperature of between -5 °C and +5 °C, e.g. about 0 CC, and the resulting mixture is stirred for a period of between 12 and 24 hours, e.g. about 16 hours, providing a compound of formula XXVII,
Figure imgf000030_0002
(XXVII)
wherein R3 and R4 are protecting groups for a hydroxy group, characterized in that R4 can be split off under reaction conditions that do not result in splitting off the protecting group R3. Finally, the compound of formula XXVll, wherein R3 and R are protecting groups for a hydroxy group, characterized in that R4 can be split off under reaction conditions that do not result in splitting off the protecting group R3, is transformed into a diene of formula VII wherein R3 and R,, have the same meaning as for the compound of formula XXVll and X is a leaving group, by transforming the primary hydroxy group in the compound of formula XXVll into a suitable leaving group X, e.g. a tosylate, a mesylate or a halogenide. For example, the compound of formula XXVll can be solved in a suitable solvent, e.g. a di-lower alkyl ether or acetonitrile or a mixture thereof, and treated at a temperature of between -5 °C and +5 °C, e.g. about 0 °C, first with triphenylphosphine and imidazole and secondly at the same temperature with iodine, furnishing a diene of formula VII wherein R3 and R4 have the same meaning as in the compound of formula XXVll and X is iodide.
Alternative Approach for the Preparation of a Ketone of Formula II
A ketone of formula II wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R is hydrogen can also be obtained by the reaction of the aldehyde of formula IX, wherein R is hydrogen and R2 and R3 are identical or different protecting groups for a hydroxy group, with a phosphonate ester of formula LVI
OCH2CF3
Alk'-O-
~P P— OCH2CF3 II
O O (LVI)
wherein Alk' is lower alkyl, preferably methyl, e.g., in the presence of a suitable base, e.g. potassium carbonate together with 18-crown-6, in a suitable solvent, like benzene or toluene together with HMPA, at a temperature between 5 °C and 40 °C, e.g. 20 °C to 25 °C, for about 1 to 5 hours, furnishing an ester of formula LVII
Figure imgf000032_0001
wherein R2 and R3 are identical or different protecting groups for a hydroxy group, R is hydrogen and Alk' is lower alkyl, preferably methyl,
followed by basic saponification of the obtained ester of formula LVII under conditions known as such, e.g. by treatment in a mixture of tetrahydrofuran and water with an alkaline base like lithium hydroxide, furnishing the acid of formula LVIII
Figure imgf000032_0002
(LVIII)
wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is hydrogen,
which finally is transferred into the ketone of formula II wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R is hydrogen by reaction with at least two equivalents of methyl lithium, e.g. in tetrahydrofurane, at a temperature between about -90 °C and - 60 °C, e.g. about -80 °C.
Alternative Approach for the Preparation of an Aldehyde of Formula IX Specific embodiments of the following method of preparing an aldehyde of formula IX are disclosed in the publication "A Practical Synthesis of (+)-DiscodermoIide and Analogues: Fragment Union by Complex Aldol Reactions" by Ian Paterson, Gordon J. Florence, Kai Geriach, Jeremy P. Scott and Natascha Sereinig, J. Am. Chem. Soc. 2001, 123, 9535-9544.
An aldehyde of formula IX wherein R4 is hydrogen, and R2 and R3 are identical or different protecting groups for a hydroxy group, can be obtained by a reaction sequence, wherein in a first step an aldehyde of formula XXlll, wherein R is a protecting group for a hydroxy group which can be split off under conditions that do not result in the removal of the protecting group R2 (see below), is reacted with a carbonic acid ester of formula XXIX
Figure imgf000033_0001
wherein Ar is aryl, preferably phenyl, which is mono-, di- or trisubstituted by lower alkyl, e.g. 2,6-di-lower alkyl phenyl, and Ri and R2 are identical or different protecting groups for a hydroxy group characterized in that the group Ri can be removed under conditions that do not result in the removal of the protecting group R2, by adding at a temperature between - 80 °C and - 120 °C, e.g. about - 100 °C, the aldehyde of formula XXlll to the solution of the carbonic acid ester of formula XXIX and a sterically hindered base, e.g., lithium 2,2,6,6- tetramethylpiperidine, in a suitable solvent, e.g. tetrahydrofuran, in the presence of lithium bromide, furnishing a β-hydroxy carbonic acid of formula XXX,
Figure imgf000034_0001
wherein Ar is aryl, preferably phenyl, which is mono-, di- or trisubstituted by lower alkyl, e.g. 2,6-di-lower alkyl phenyl, wherein Ri, R2 and R represent different protecting groups for a hydroxy group characterized in that the groups R and R4 can be removed under conditions that do not result in the removal of the protecting group R2.
In a second step, the obtained β-hydroxy carbonic acid of formula XXX is reduced in order to furnish a diol of formula XXXI,
Figure imgf000034_0002
wherein Ri, R2 and I 4 represent different protecting groups for a hydroxy group characterized in that the groups Ri and R can be removed under conditions that do not result in the removal of the protecting group R2, and R13 is hydrogen, by solving the compound of formula XXX in a suitable solvent, e.g. tetrahydrofuran, and then adding a reduction agent which is capable of transforming an aryl ester into the corresponding primary alkohol, e.g., adding a solution of lithium aluminium hydride in tetrahydrofuran at a temperature between -60 °C and -100 °C, e.g. at about -78 °C.
In a third step, the obtained diol of formula XXXI is reacted with a compound of formula XXXII RisHal (XXXII)
wherein R13 is -SO2-aryl wherein the aryl radical is unsubstituted or substituted by alkyl, and Hal represent halogen, under reaction conditions known as such, e.g. by adding at about room temperature the reagent XXXII to a solution of the diol of formula XXXI in dichloromethane, obtaining a sulfonate of formula XXXI wherein Ri, R2 and P represent different protecting groups for a hydroxy group characterized in that the groups Ri and R4 can be removed under conditions that do not result in the removal of the protecting group R2, and Ri3 is -SO2-aryl wherein the aryl radical is unsubstituted or substituted by alkyl.
In a fourth step, the resulting sulfonate of formula XXXI is reduced, e.g., by treatment with NaBH4) LiBH4, diisobutyl aluminium hydride, LiB(ethyl)3H, Zn, tributyl tin hydride or, preferably, LiAIH4 at a temperatur between about -20 °C and 0 °C, furnishing a triene of formula V,
Figure imgf000035_0001
wherein Ri, R2 and R4 represent different protecting groups for a hydroxy group characterized in that the groups Ri and R4 can be removed under conditions that do not result in the removal of the protecting group R2, and R3 represents hydrogen.
Suitable reaction conditions for a reduction utilising LiAIH are, for example, described in J. Org. Chem. 1980, 45, 2550 to 2551 or also J. Am. Chem. Soc. 1951, 73, on page 2874 (2nd Example described there). NaBH4 can, for example, generally be employed in dimethyl sulfoxide or sulfolane at a temperature between 15 °C and 100 °C, e.g. 25 °C or 85 °C, and tributyl tin hydride generally in refluxing 1 ,2-dimethoxyethane (DME) in the presence of sodium iodide. ln a fifth step, the triene of formula V, wherein Ri, R2 and R represent different protecting groups for a hydroxy group characterized in that the groups Ri and R4 can be removed under conditions that do not result in the removal of the protecting group R2, and R3 represents hydrogen, can be transferred into a triene of formula V, wherein Ri, R2 and R4 have the same meanings and R3 represents a protecting group for a hydroxy group, which is stable under conditions under which the groups R and R can be removed, e.g., by reaction of the triene of formula V with a reagent of the structure R3-triflate in the presence of a base, e.g. tri-lower alkyl amine, in a suitable solvent, e.g. dichloromethane, at a temperature between -60 °C and -100 °C, e.g. about -80 °C.
In a sixth step, the resulting triene of formula V, wherein Ri, R2, R3 and R represent different protecting groups for a hydroxy group characterized in that the groups Ri and R4 can be removed under conditions that do not result in the removal of the protecting groups R2 and R3, is then transferred into a diol of formula V, wherein R^ and R4 are hydrogen, and R2 and R3 are identical or different protecting groups for a hydroxy group, by selectively splitting off the protecting groups Ri and R4.
Finally, the primary alcohol in the diol of formula V, wherein Ri and R4 are hydrogen, and R2 and R3 are identical or different protecting groups for a hydroxy group, is selectively oxidised furnishing the aldehyde of formula IX wherein R is hydrogen, and R2 and R3 are identical or different protecting groups for a hydroxy group. Suitable oxidising conditions are known as such, e.g., a solution of the diol of formula V in dichloromethane can be treated with 2,2,6,6- tetramethyl-1-piperinyloxy (TEMPO), followed by iodobenzene acetate at a temperature between 10 °C and 30 °C, e.g. about 20 °C.
Alternative Approach for the Preparation of an Aldehyde of Formula XXlll, wherein R4 is p- Methoxybenzyl
Figure imgf000036_0001
(XXlll) An aldehyde of formula XXlll wherein R4 is p-methoxybenzyl can be obtained by a reaction sequence starting with a carboxylic acid ester of formula XXXIII,
H O. .OR 15
° (XXXIII)
wherein R15 is lower alkyl, e.g. methyl, which is solved in a suitable solvent, e.g. dichloromethane, and reacted in the presence of catalytic amounts of an acid, e.g. triflic acid, with Rι6-2,2,2-trichloroacetimidate at a temperature between 10 °C and 30 °C, e.g. about 20 °C, furnishing a carbonic acid ester of formula XXXIV,
R1°\^^/0R15
O (XXXIV)
wherein Ri is a protecting group for a hydroxy group that can be transformed into a protecting group for a diol, e.g. p-methoxybenzyl, and R15 is lower alkyl, e.g. methyl.
In a second step, the carbonic acid ester of formula XXXIV, wherein Ri is a protecting group for a hydroxy group that can be transformed into a protecting group for a diol, e.g. p- methoxybenzyl, and Rι5 is lower alkyl, e.g. methyl, is transferred into the amide of formula XXXV,
Figure imgf000037_0001
wherein R is a protecting group for a hydroxy group that can be transformed into a protecting group for a diol, e.g. p-methoxybenzyl, by reaction in a suitable solvent like toluene or benzene with N,O-dimethyihydroxylamine hydrochloride in the presence of an equal amount of trimethylaluminium at a temperature between -10 °C and +10 °C, e.g. about 0 °C.
The obtained amide of formula XXXV, wherein Ri has the meaning as provided above for a compound of formula XXXIV, is then in a third step subject of a Grignard reaction employing ethylmagnesium bromide under conditions known as such, e.g. a solution of the Grignard reagent in diethylether or tetrahydrofuran is dropped to the solution of the amide of formula XXXV in the same solvent at a temperature of about 0°C in which process the reaction mixture can be punctually warmed or iodine can be added in order to start the reaction. The Grignard reaction is stopped after a period of about 0.5 to 3 hours, e.g. after about 1 hour, providing a ketone of formula XXXVI,
Figure imgf000038_0001
(XXXVI)
wherein Ri has the meaning as provided above for a compound of formula XXXIV.
One example for the preparation of a ketone of formula XXXVI starting from a carboxylic acid ester of formula XXXIII is disclosed in the examples on pages 11300 and 11301 of J. Am. Chem. Soc. 116, 25, 1994, 11287, authors Ian Paterson et al, which publication is included herein by reference.
In a fourth step, the ketone of formula XXXVI, wherein Ri has the meaning as provided above for a compound of formula XXXIV, is transferred into a β-hydroxy ketone of formula XXXVII
Figure imgf000038_0002
(XXXVII) wherein Ri has the meaning as provided above, by a boron-mediated aldol reaction with formaldehyde. For this purpose, the ketone of formula XXXVI, can be, e.g., added at a temperature between -10 °C and +10 °C, e.g. about 0 °C, to a mixture of dicyclohexylboron chloride and a tri-lower alkyl amine, e.g. triethylamine, in a suitable solvent, e.g. diethylether, and after a period between about 1 and 3 hours, formaldeyhde is added at a temperature between -60 °C and -100 °C, e.g. about -80 °C. After about one hour, the reaction mixture is warmed to a temperature between -10 °C and +10 °C, e.g. about 0 °C, and a lower alcohol, e.g. methanol, a pH 7 buffer and finally hydrogen peroxide is added.
In a fifth step, the β-hydroxy ketone of formula XXXVII wherein Ri has the meaning as provided above for a compound of formula XXXIV is further reduced to the corresponding diol of formula XXXVIII,
Figure imgf000039_0001
(XXXVII!)
wherein Ri has the meaning as provided above, e.g., the β-hydroxy ketone of formula XXXVII, can be reacted with the reducing agent sodium triacetoxyborohydride in a suitable solvent, e.g. tetrahydrofuran, at a temperature between -10 °C and +10 °C, e.g. about 0 °C, under reaction conditions known as such.
In a sixth step, the diol of formula XXXVIII, wherein Ri has the meaning as provided above for a compound of formula XXXIV, is reacted with tert-butyl-dimethyl-silyl (TBDMS) chloride, triisopropylsilyl (TIPS) chloride or thexyldimethylsilyl (TDS) chloride, preferably TBDMS chloride in the presence of imidazole or another suitable base, providing an alcohol of formula XXXIX,
Figure imgf000039_0002
(XXXIX) wherein Ri is a protecting group for a hydroxy group that can be transformed into a protecting group for a diol and R14 is TBDMS, TIPS or TDS.
In a further step, the obtained alcohol is oxidized with a reagent that is capable of transforming the protecting group Ri into a protecting group for a diol, e.g., if R-i represents p- methoxy-benzyl, the reaction can be accomplished with 2,3-dichloro-5,6-dicyano-1 ,4,-benzo- quinone, furnishing a compound of formula XL.
Figure imgf000040_0001
wherein Rι4 is TBDMS, TIPS or TDS and R16 is a protecting group for a diol, e.g. p-methoxy phenyl.
In a further step, the obtained compound of formula XL is reacted with a reagent that is capable of transforming the protecting group for a diol into a protecting group for a hydroxy group, e.g., if Rι6 represents p-methoxy phenyl, the reaction can be accomplished with diisobutyl aluminium hydride in tetrahydrofuran under conditions known as such, furnishing an alcohol of formula XLI,
R 14 ' / /OH
O.
R4 (XLI)
wherein R 4 is TBDMS, TIPS or TDS and R is a protecting group for a hydroxy function, e.g. p-methoxy benzyl. ln the next step, the alcohol function in the compound of formula XLI, wherein RM is TBDMS, TIPS or TDS and R4 is a protecting group for a hydroxy function, e.g. p-methoxy benzyl, is oxidized to the corresponding aldehyde. The oxidation of the alcohol function in the compound of formula XLI can be achieved, e.g., by oxidation with Collin's reagent , eerie ammonium nitrate (for reaction conditions see, e.g. Trahanovsky et al, J. Chem. Soc. 5777, 1965), N-methyl-morpholineoxide in the presence of a suitable Ru complex (for reaction conditions see, e.g. Sharpless et al, Tetrahedron Lett. 2503, 1976), and in particular, with DMSO in conjunction with a further suitable reagents, like acetic anhydride, oxalyl chloride, or, especially, a S03-pyridine complex in the presence of a tertiary amine as defined above, preferably triethylamine, providing an aldehyde of formula XLI I
Figure imgf000041_0001
(XLIi)
wherein R14 is TBDMS, TIPS or TDS and R4 is a protecting group for a hydroxy function, e.g. p-methoxy benzyl.
In the following step, the obtained aldehyde of formula XLII is transformed into the diene of formula XLIII,
Figure imgf000041_0002
(XLIII)
wherein R14 is TBDMS, TIPS or TDS and R is a protecting group for a hydroxy function, e.g. p-methoxy benzyl, e.g., by a Wittig reaction, a Peterson olefination or, in particular, by a Nozaki-Hiyama-Kishi reaction. For the latter reaction, the aldehyde of formula XLII is solved in a suitable inert solvent, e.g., tetrahydrofurane, and reacted at a temperature between -5 °C and +5 °C, e.g. about 0 °C, with CrCI2 and (l-halo-allyl)-tri-lower alkyl silane, e.g. (1- bromo-allyl)-trimethylsilane, for a period of between 2 and 6 hours, e.g., about 4 hours, and, afterwards, the obtained intermediate solved in a suitable inert solvent, e.g., tetrahydrofurane, is added to a suspension of a strong base, e.g. potassium hydride, solved in a suitable inert solvent, e.g., tetrahydrofurane, at a temperature between -5 °C and +5 °C, e.g. about 0 °C.
In the two final steps, the protecting group Ru is detached from the diene of formula XLIII under conditions known as such and the obtained free hydroxy function is oxidized to the corresponding aldehyde under conditions as reported for the preparation of the aldehyde XLII by oxidation of the alcohol XLI (see above), furnishing an aldehyde of formula XXlll wherein R4 is a protecting group for a hydroxy function, e.g. p-methoxy benzyl.
Preparation of the Carbonic Acid Ester of Formula XXIX
The carbonic acid ester of formula XXIX wherein Ar is aryl, preferably phenyl, which is mono-, di- or trisubstituted by lower alkyl, e.g. 2,6-di-lower alkyl phenyl, and Ri and R2 are identical or different protecting groups for a hydroxy group characterized in that the group Ri can be removed under conditions that do not result in the removal of the protecting group R2, can be prepared by the following reaction sequence.
In a first step, the β-hydroxy ketone of formula XXXVll, wherein Ri is a protecting group for a hydroxy group characterized in that the group Ri can be removed under conditions that do not result in the removal of the protecting group R2, is selectively oxidized to the corresponding aldehyde of formula XLIV,
Figure imgf000042_0001
wherein Ri has the meaning as provided above for a compound of formula XXIX, e.g., by reaction with 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and iodobenzene diacetate, e.g., in dichloromethane at a temperature between - 5°C and + 5 °C, e.g. 0 °C. ln a second step, the obtained aldehyde of formula XLIV, wherein Ri has the meaning as provided above for a compound of formula XXIX, is subjected to a Still-Gennari olefination reaction, the reaction conditions of which are known as such. For example, the olefination can be carried out by solving the reagent of formula XLV
(F3CCH20)2P(O)CH(Me)CO-OAIk (XLV)
wherein Alk represents alkyl, preferably lower alkyl like methyl, in a suitable solvent, e.g. tetrahydrofuran, together with a strong base, e.g. sodium hydride or, preferably, potassium hexamethyldisilazane in the presence of 18-crown-6, and adding at a temperature between - 100°C and - 60 °C, e.g. about -80 °C, the aldehyde of formula XLIV solved in the same solvent, furnishing the alcohol of formula XLVI
Figure imgf000043_0001
wherein Ri has the meaning as provided above for a compound of formula XXIX, R2 is hydrogen and Alk represents alkyl, preferably lower alkyl like methyl.
In a third step, the obtained alcohol of formula XLVI is reacted with a reagent introducing a protecting group for a hydroxy group R2, which group is stable under conditions which effect cleavage of the protection group Ri, thus furnishing a compound of formula XLVI, wherein Ri has the meaning as provided above for a compound of formula XXIX, R2 is protecting group for a hydroxy group which group is stable under condition which effect cleavage of the protection group Ri, and Alk represents alkyl, preferably lower alkyl like methyl. For example, if R1 represents p-methoxybenzyl, the alcohol of formula XLVI can be reacted with te/f-butyl-dimethyl-siϊyl (TBDMS) chloride in the presence of imidazole or, preferably, TBDMS triflate in the presence of 2,6-lutidine under conditions known as such, thus establishing TBDMS as the protecting group R2.
In a fourth step, the compound of formula XLVI, wherein Ri has the meaning as provided above for a compound of formula XXIX, R2 is protecting group for a hydroxy group which group is stable under condition which effect cleavage of the protection group Ri, and Alk represents alkyl, preferably lower alkyl like methyl, is reacted with a reducing agent which is capable of transforming a carbonic acid ester into the corresponding alcohol under reaction conditions known as such, preferably those reducing agents mentioned herein above, more preferably diisobutylaluminium hydride, furnishing an alcohol of formula XLVIl,
Figure imgf000044_0001
(XLVIl)
wherein Ri has the meaning as provided above for a compound of formula XXIX and R2 is a protecting group for a hydroxy group which group is stable under conditions which effect cleavage of the protection group Ri.
The reaction of the alcohol of formula XLVIl, wherein Ri and R2 have the meanings as provided above for a compound of formula XLVIl, with (Hal)4C, wherein Hal represents halo, preferably bromo, in the presence of triphenylphosphine and optionally a base under conditions known as such, results in the halide of formula XLVI 11
Figure imgf000044_0002
(XLVIII)
wherein Ri and R2 have the meanings as provided above for a compound of formula XLVIl and Hal represents halo, preferably bromo.
In the final step, the halide of formula XLVIII, wherein Ri and R2 have the meanings as provided above for a compound of formula XLVIl, and Hal represents halo, preferably bromo, is reacted with the lithium enolate of a compound of formula IL,
Figure imgf000045_0001
wherein Ar is aryl, preferably phenyl, which is mono-, di- or trisubstituted by lower alkyl, e.g. 2,6-di-lower alkyl phenyl, e.g. by reacting first the compound of formula IL in a suitable solvent, e.g. tetrahydrofuran, in the presence of N,N,N',N',N",N"-hexamethylphosphotriamide with a strong lithium base, preferably lithium diisopropylamide, at a temperature between - 100°C and - 60 °C, e.g. about -80 °C, in order to obtain the carbonic acid ester of formula XXIX wherein Ar is aryl, preferably phenyl, which is mono-, di- or trisubstituted by lower alkyl, e.g. 2,6-di-lower alkyl phenyl, and Ri and R2 are identical or different protecting groups for a hydroxy group characterized in that the group R1 can be removed under conditions that do not result in the removal of the protecting group R2.
Preparation of the Aldehyde of Formula III wherein R- represents R8-0-
The aldehyde of formula III
Figure imgf000045_0002
wherein R5 is a protecting group for a hydroxy group, and R represents R8-O-, wherein R8 represents alkyl, can be prepared by the following reaction sequence.
In the first step the aldehyde of formula XLIV,
Figure imgf000045_0003
wherein R is a protecting group for a hydroxy group, is oxidized to the corresponding acid by reaction with an oxidizing agent, e.g., potassium permanganate in acid, basic or neutral solution (depending on the nature of the protecting group Ri), silver oxide, or, preferably, sodium chlorite, under reaction conditions known as such, providing an carboxylic acid of formula L,
Figure imgf000046_0001
wherein R, is a protecting group for a hydroxy group.
In a second step, the obtained carboxylic acid of formula L is transferred into a carboxylic acid ester of formula LI,
Figure imgf000046_0002
wherein R is a protecting group for a hydroxy group and R represents R8-O-, wherein R8 represents alkyl, preferably methyl, by reaction with a diazo compound of the formula LI I
R8CN2 (LI I)
wherein R8 represents lower alkyl, in a suitable solvent at a temperature between - 10°C and +30 °C, e.g. about +10 °C.
An ester of formula LI, wherein R represents methoxy, alternatively can be prepared by reaction of the carbonic acid of formula L with methyl iodide and a suitable base, e.g. potassium carbonate, thus avoiding the hazardous diazomethane. ln a third step, the hydroxy function in the carboxylic acid ester of formula LI is protected by reaction with a reagent introducing a protecting group which is stable under conditions under which the protecting group Ri can be cleaved, e.g., tert-butyl-dimethyl-silyl (TBDMS) chloride, triisopropylsilyl (TIPS) chloride or thexyldimethylsilyl (TDS) chloride, preferably TBDMS triflate in the presence of 2,6-lutidine or another suitable base, under conditions known as such, furnishing a carboxylic acid ester of formula LI II
Figure imgf000047_0001
wherein R, is a protecting group for a hydroxy group, R5 is a protecting group for a hydroxy group which is stable under conditions under which the protecting group Ri can be cleaved, and R represents R8-0-, wherein R8 represents alkyl, preferably methyl.
In a fourth step, the protecting group Ri is splitt off under conditions under which the protecting group R5 remains untouched. For example, if Ri represents p-methoxybenzyl (PMB) and R5 represents TBS or another oxidatively stable protecting group, selective deprotection can be achieved by reaction with a suitable oxidation reagent which is known to splitt of a PMB group, e.g. 2,3-dichloro-5,6-dicyano-1,4,-benzoquinone (DDQ). The person skilled in the art is aware of numerous further combinations of two protecting groups for a hydroxy function in which the one group can be cleaved whereas the second group remains in place. All such combinations are incldued in the present invention. The fourth step furnishes an alcohol of formula LIV
Figure imgf000047_0002
wherein R5 is a protecting group for a hydroxy group and R represents R8-O-, wherein R8 represents alkyl, preferably methyl. ln the final step, the obtained alcohol of formula LIV is oxidized to the aldehyde of formula III wherein R5 is a protecting group for a hydroxy group and R- represents R8-0- by reaction with a suitable oxidizing agent, e.g., by oxidation with Collin's reagent , eerie ammonium nitrate (for reaction conditions see, e.g. Trahanovsky et al, J. Chem. Soc. 5777, 1965), with DMSO in conjunction with a further suitable reagents, like acetic anhydride, oxalyl chloride, or, especially, a S03-pyridine complex in the presence of a tertiary amine as defined above, preferably triethylamine, or, especially, with N-methyl-morpholineoxide in the presence of a suitable Ru complex, e.g. tetrapropylammonium perruthenate (for suitable reaction conditions see, e.g., Ley et ai, Synthesis 1994, 639).
Final deprotection and δ-lactonisation of a diol of formula LV wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group, R4 is hydrogen or H2NC(O)-, and R represents (a) R6-O-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5, (b) R8-0-, wherein R8 represents alkyl, or (c) a substructure of formula Ilia wherein Rg represents alkyl or aryl, Rio and R represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom; can be achieved, e.g., by treatment with the solution of a hydrogenfluoride-pyridine adduct in tetrahydrofuran for a period of about 12 to 18 hours, e.g. about 16 hours, or by treatment with a solution of a hydrogenchloride in a lower alcohol like methanol for a period of about 2 to 6 days, e.g. about 4 days.
As mentioned before, the final steps of preparing a lactone of formula I,
Figure imgf000048_0001
wherein the radicals R2, R3, R» and R5 have the meanings as provided for a compound of formula IV above, comprise a diastereoselective reduction followed by a lactonization reaction or a lactonization reaction followed by a diastereoselective reduction of a tetraene of formula IV
Figure imgf000049_0001
wherein the radicals and symbols have the meanings as provided for a compound of formula IV above. In a preferred embodiment of the invention, the tetraene of formula IV is first lactonised, e.g., by treatment with a mild acid, such as acetic acid, furnishing a ketone of formula LIX
Figure imgf000049_0002
wherein the radicals R2, R3, R4 and R5 have the meanings as provided for a compound of formula IV above, and thereafter the obtained ketone of formula LIX is reduced to provide the compound of formula I, wherein the radicals R2l R3, R4 and R5 have the meanings as provided for a compound of formula IV above, e.g., by reaction with potassium Selectride, under conditions known as such. Hence, the present invention also relates to a ketone of formula LIX, wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group, and R4 is hydrogen or H2NC(0)-.
The following examples are for purposes of illustration only and are not intended to limit in any way the scope of the instant invention. Starting materials can be purchased or prepared by the methods mentioned hereinafter.
Abbreviations
AcOEt ethyl acetate aqu. aqueous
9-BBN 9-borabicyclo[3.3.1]nonane brine saturated sodium chloride solution bu butyl cHex cyclohexyl
CSA 10-camphorsulfonic acid
DIBALH diisobutylaluminium hydride
DMAP dimethylaminopyridine
DMF dimethylformamide
DMSO dimethyl sulfoxide
Et ethyl h hour(s)
HMPA N , , N', N', N", N"-hexamethylphosphotriamide
HRMS high resolution mass spectrometry
Ipc isopinocampheyl isoPr isopropyl min minute(s) m.p. melting point
Me methyl
NaHDMS sodium hexamethyldisilazane
NMR nuclear magnetic resonance
PE petrol ether
PMB p-methoxybenzyl PTLC preparative thin layer chromatography
RT room temperature sat. saturated
TBDMS tert-butyl-dimethylsilyl
TBDMSOTf tert-butyl-dimethylsilyl-trifluoromethanesulfonate
TBME tert-butyl methyl ether
TBS tert-butyl-dimethylsilyl
Tf trifluoromethanesulfonate
TEMPO 2,2,6,6-tetramethylpiperidine 1-oxyl
TES triethylsilyl
THF tetrahydrofurane
TLC thin layer chromatography
TMP 2,2,6,6-tetramethylpiperidine
Example 1 : (3R4S,5SH-(te/f-Butyl-dimethyl-silanyloxy)-3,5-dimethyl-tetrahvdro-pyran-2- one
To a solution of the alcohol of stage 1.4 (2.08 g, 3.85 mmol) in 40 mL of THF at 0 °C under an atmosphere of Ar a solution of terf-BuOK (1.5 M in THF, 77 μL, 77 μMol) is added. The clear solution is stirred for 1h and allowed to warm up to 23 °C. A white precipitate (cleaved oxazolidinone) forms gradually. The reaction mixture is diluted with 50 mL of hexane and filtered. The residue is washed with aqu. sat. NaCl. The filtrate is collected and the organic layer is dried over MgS0 and partially concentrated in vacuo. A white precipitate forms during the concentration. The mixture is filtered and the residue is washed with 5 mL of hexane. The filtrate is collected and concentrated in vacuo to give the desired lactone as a colorless oil which solidifies upon conservation at 4 °C providing a solid having a m.p. of 53- 54 °C.
Stage 1.1 : (f?)-3-r(2f?.3R)-3-Hvdroxv-2.4-dimethvl-pent-4-enovll-4-isopropyl-5,5-diphenvl- oxazolidin-2-one
A solution of 14.9 mL (87 mmol) of diisoproylethylamine in 30 mL of CH2CI2 under an atmosphere of argon is treated sequentially at 5 °C over 10 min with a 1.0 M solution of n-
Bu2BOTf in CH2CI2 (78 mL, 78 mmol) and at -78 °C over 15 min with a solution of (R)-4- isopropyl-5,5-diphenylpropionyloxazolidin-2-one (20.2g, 60 mmol, prepared according to T. Hintermann, D. Seebach, Helv. Chim. Acta 1998, 81, 2093) in 60 mL of CH2CI2 to give a clear orange solution. After 10 min at -78 °C, the solution is warmed to 0 °C and is stirred for 1 h, after which it is recooled to -78 °C. A solution of methacrolein (14.8 L, 180 mmol) in 20 ml of CH2CI2 is then added slowly over a period of 30 min. After stirring for 30 min, the reaction mixture is warmed to 0 °C and is stirred for 1 h. Phosphate buffer (pH 7, 60 L), MeOH (180 mL) and MeOH/35% H2O2 (2:1 v/v, 180 mL) are added sequentially at 0 °C. After stirring for 3 h at RT, the mixture is recooled to 0 °C and treated with 40% aqu. NaHS03 (80 mL). The volatiles are removed in vacuo and the residual aqu. phase is extracted with toluene (3 x 200 L). The combined organic layers were washed with 1N HCI (60 mL), saturated aqu. NaHC03 (60 mL) and brine (60 mL), dried over MgSO4, filtered and concentrated in vacuo to give the title compound as slightly yellowish crude solid residue. A sample of crude alcohol prepared as above is purified by flash-chromatography (Si02, hexane/AcOEt 3:1) to afford the title compound as white crystals, m.p. of 99.5-100.0°C.
Stage 1.2: (R)-3-r(2R.3S.4S)-3,5-Dihvdroxv-2,4-dimethvl-pentanovn-4-isopropyl-5. 5- diphenyl-oxazolidin-2-one
A solution of thexyl borane in THF [prepared in situ by dropwise addition at 0 °C of 2,3- dimethyl-2-butene (37.2 g, 442 mmol) to BH3 HF (1 M in THF, 442 mL, 442 mmol) followed by 1 h stirring at 0 °C] at 0 °C under an atmosphere of argon is treated dropwise over a period of 40 min with a solution of the title compound of stage 1.1 (106 g, 260 mmol) in THF (100 mL). After stirring at 0 °C for 2 h, the reaction mixture is treated sequentially and under temperature control (ca 0 °C, cooling bath at -20 °C) with EtOH/THF 1 :1 v/v (520 mL) over a period of 25 min, pH 7 phosphate buffer (520 mL) over a period of 15 min and 35% aqueous hydrogen peroxide (250 L) over a period of 20 min. Thereupon, the resulting solution is stirred successively at 0 °C for 1 h and at 23 °C for 14 h before being extracted twice with hexane (1500 mL and 1000 mL). The organic extracts are washed with Na2S203 (1000 mL and 600 mL) and pH 7 phosphate buffer (600 mL), combined, dried (MgSO4) and concentrated in vacuo. The residue is dissolved in a mixture of CH2CI2 (1000 mL) and H20 (600 mL) and the pH of the water layer of the resultant two-phase mixture is increased from 4.1 to 11.2 by dropwise addition monitored with a pH-meter over a period of 1 h of 1 N NaOH (110 mL). After, the pH of the aqueous layer remains stable at 11.2 for 15 min, the layers are separated. The organic layers are washed with aqu. sat. NH4CI (300 mL), aqu. sat. NaCl (300 mL) combined, dried (MgSO4) and concentrated in vacuo to give the title compound as colorless crystals. This material is used without further purification; Rf = 0.27 (Si02, 1:1 heptane-AcOEt).
Stage 1.3: (ffl-3-r(2R3S.4S)-3.5-Bis-(tert-butvl-dimethvl-silanvloxv)-2.4-dimethvl-pentanovll- 4-isopropyl-5,5-diphenyl-oxazolidin-2-one
To a solution of crude diol of stage 1.2 (25g) and 2,6-lutidine (37.5 mL, 323 mmol) in CH2CI2 (150 mL) at 0 °C under an atmosphere of argon TBDMSOTf (41 mL, 234 mmol) is added dropwise over a period of 35 min. After stirring at 0 °C for 2 h, the reaction mixture is worked-up. Aqueous 1N HCI (150 mL) is added dropwise at 0 °C over a period of 20 min (exothermic) followed by heptane (200 mL). The aqueous layer is extracted with heptane (100 mL). The organic extracts are combined, washed with aqu. NaHC03 (8% m/m solution, 200 L) and brine (200 mL), dried over MgS04 and concentrated in vacuo. Re-crystallization of the residue (42.5 g) in MeOH (150 mL, dissolution at 50 °C, filtration at 0 °C, washing with 40 mL of MeOH) provides the title compound as colorless crystals with a m.p. of 104-105 °C.
Stage 1.4: ( ?)-3-r(2R3S.4S)-3-(tert-Butvl-dimethvl-silanvloxv)-5-hvdroxv-2.4-dimethvl- pentanoyl]-4-isopropyl-5,5-diphenyl-oxazolidin-2-one
To a solution of the compound of stage 1.3 (59.2 mg, 0.071 mmol) in MeOH (1 mL) at 0 °C dichloroacetic acid (33.5 mg, 0.354 mmol) is added. After stirring at 0 °C for 1 h and 45 min the reaction mixture is quenched with sat. aqu. NaHC03 (6 mL) and extracted with TBME (2 x 4 mL). The organic extracts are washed with brine (10 mL), combined, dried (MgS04) and concentrated in vacuo to provide the desired alcohol as colorless crystals. This material is used without further purification
Example 2: (3f?.4S,5S)-3.5-Dimethyl-4-triethylsilanyloxy-tetrahvdropyran-2-one
To a solution of 46.25 g (85.7 mmol) of the compound of stage 2.2 in THF (270 mL) at 0 °C under an atmosphere of argon a solution of t-BuOK (1 M in THF, 1.71 mL, 1.7 mmol) is added. The resulting reaction mixture is stirred for 30 min at 0 °C. A precipitate is removed by filtration at 0 °C followed by washing with hexane (80 mL). The filtrate is collected, hexane (800 mL) is added and the organic phase is washed with brine (2 x 300 mL). The organic layer is dried over MgS04 and concentrated under reduced pressure to 15% of its initial mass which causes the precipitation of a colorless solid. The mixture is filtered and the residue is washed with hexane (50 mL). The filtrate is collected and concentrated in vacuo. Purification by flash-chromatography (500 mL of Si02, 9:1 hexane/AcOEt) provides the title lactone as a pale yellowish oil. Pure oxazolidinone is reisolated from the filtration of the reaction mixture in 69 % yield.
Stage 2.1 : (R)-3-f(2R.3S.4S)-2.4-dimethvl-3.5-bis-triethvlsilanvloxv-pentanovl]-4-isopropyl- 5,5-diphenyl-oxazolidin-2-one
To a turbid solution of crude compound from stage 1.2 (50.9 g) and 2,6-lutidine (73.7 g, 0.69 mol) in CH2CI2 (150 L) at -78 °C under an atmosphere of argon TESOTf (140.4 g, 0.53 mol) is added dropwise over a period of 35 min. The reaction mixture is stirred for 2 h at -78°C, after which the reaction mixture is allowed to warm up at 0 °C within 30 min. CH2CI2 (300 mL) and aqueous 1N HCI (700 mL) are added sequentially. The aqu. layer is extracted with CH2CI2 (2 x 500 mL). The organic layers are washed with 1N HCI (700 mL), sat. aqu. NaHC03 (400 mL) and sat. aqu. NaCl (400 mL), combined, dried over MgS04 and concentrated in vacuo to give the desired bis-silyl ether as a mixture of crystals and oil. This material was used without further purification; Rf = 0.59 (Si02, 3:1 heptane-AcOEt).
Stage 2.2: (R)-3-r(2r?.3S.4S)-5-hvdroxv-2.4-dimethvl-3-triethvlsilanvloxv-pentanovl]-4- isopropyl-5,5-diphenyl-oxazo!idin-2-one
Acetic acid (150 g, 2.50 mol) is added to a turbid emulsion of crude compound from stage 2.1 (117.2 g) in a mixture of THF/CH3OH/H20 5:5:1 v/v/v (300 mL) at 23 °C. The resulting solution is heated at 50 °C for 5 h. The reaction mixture is quenched with H20 (800 mL) and extracted with TBME (2 x 500 mL). The organic extracts are washed with aqu. sat. NaHC03 (400 mL) and aqu. sat. NaCl (400 mL), combined, dried (MgS04) and partially concentrated under reduced pressure initiating the crystallization of the desired alcohol. The suspension is stirred at 0 °C for 14 h. Filtration and washing of the residue with TBME (30 mL) provides the desired alcohol as colorless crystals; Rf = 0.28 (Si02, 3:1 heptane-AcOEt).
Example 3: (2/?.3g,4 ?)-3-Cte/ -Butyl-dimethyl-silanyloxy)-2.4-d?methyl-5-oxo-pentanoic acid methoxy-methyl-amide
A solution of crude product from stage 3.1 (2.18 g, 6.8 mmol) in CH2CI2 (6.5 mL) at 0 °C under an atmosphere of argon is treated sequentially with triethylamine (3.8 mL, 27.3 mmol), DMSO (2.4 mL) and a solution of sulfur trioxide-pyridine complex (3.26 g, 20.5 mmol) in DMSO (11.2 mL) which is added dropwise over a period of 10 min. After stirring at 0 °C for 1 h and 30 min, the reaction mixture is diluted with TBME (50 mL). A mixture of aqu. NaHS0 (1 M, 25 mL) and H20 (7 mL) is added dropwise at 0 °C and the resulting mixture is stirred for 10 min. The layers are separated and the aqueous layer is extracted with TBME (50 mL). The organic extracts are washed with aqu. NaHCO3 (8% m/m solution, 40 mL) and aqu. sat. NaCl (60 mL), combined, dried (MgS0 ) and concentrated in vacuo. The residue is purified by flash-chromatography (200 mL of SiO2, 3:1 hexane/AcOEt) to give the desired aldehyde as a pale yellowish oil which crystallizes upon conservation at 4 °C; Rf = 0.32 (Si02, 6:4 heptane-AcOEt).
Stage 3.1: (2R,3S,4S)-3-(ferf-Butyl-dimethyl-silanyloxy)-5-hydroxy-2,4-dimethyl-pentanoic acid methoxy-methyl-amide
A solution of 1.80 g (6.96 mmol) of the product of Example 1 in THF (23 L) at 23 °C under an atmosphere of Ar is treated with Λ/.O-dimethylhydroxylamine hydrochloride (1.05 g, 10.79 mmol) and the resulting suspension is cooled at -15 °C. A solution of isopropylmagnesium chloride in THF (2 M, 10.5 mL, 20.9 mmol) is then added dropwise over a period of 40 min. The resulting solution is further stirred at a temperature between -15 °C and -10 °C for 1 h and 20 min, diluted with TBME (20 mL), followed by addition of 1:1 v/v mixture of aqu. sat. NH4CI and water (40 mL). The mixture is warmed to 23 °C and stirred until the salts have dissolved. The layers are separated and the aqueous layer is extracted with TBME (15 mL). The organic extracts are washed with aqu. sat. NaCl (3 x 25 mL), combined, dried (MgS0 ) and concentrated in vacuo to give the title compound as a pale yellowish oil; Rf= 0.18 (Si02, 1 :1 heptane-AcOEt).
Example 4: 2R.3S.4R)-3-(tert-Butvf-dimethyl-sifanyloχy)-5-<'(R)-4-isopropyl-2-oxo-5.5- diphenyl-oxazolidin-3-yl)-2.4-dimethyl-5-oxo-pentanal
A solution of 1.72 g (3.19 mmol) of the product of stage 1.4 in CH2CI2 (8 mL) at 0 °C under an atmosphere of Ar is treated sequentially with triethylamine (1.78 mL, 12.8 mmol), DMSO (1.13 mL) and a solution of sulfur trioxide-pyridine complex (1.52g, 9.6 mmol) in DMSO (5.2 mL) which is added dropwise over a period of 15 min. After stirring at 0 °C for 3 h, the reaction mixture is diluted with TBME (20 mL). A mixture of aqu. NaHS04 (1 M, 12.5 mL) and H20 (3.1 mL) is added dropwise over a period of 10 min. The aqu. layer is extracted with TBME (20 mL). The organic phases are washed with cold aqu. NaHC03 (8% m/m, 20 L) and cold aqu. sat. NaCl (2 x 25 mL), combined, dried (MgS04) and concentrated in vacuo. The residue is purified by flash-chromatography (30 g of SiO2, 95:5 heptane/AcOEt) to give the desired aldehyde as a white foam; Rf = 0.51 (Si02, 7:3 heptane-AcOEt).
Example 5: (Z)-(4S.5 6S)-5-ffert-Butyl-dimethyl-silanyloxy)-2-iodo-4.6-dimethyl-7-triethyl- silanyloxy-hept-2-ene
A suspension of ethyltriphenylphosphonium iodide (10.06 g, 24.0 mmol) in THF (100 mL) at 23 °C under an atmosphere of argon is treated dropwise with NaHMDS (2 M in THF, 12.5 mL, 25 mmol) whereas the suspension develops immediately an intense orange color and dissolves gradually. After stirring at 23 °C for 30 min, the resulting deep-orange solution is added dropwise to a solution of iodine (6.05 g, 24.0 mmol) in THF (200 mL) at -78 °C over a period of 1 h and 15 min, whereas (l-iodoethyl)-triphenylphosphonium iodide precipitates as a brown solid. After stirring the resulting suspension at -78 °C for 15 min, NaHMDS (2 M in THF, 12.0 mL, 24.0 mmol) is added dropwise at -78 °C over a period of 10 min, whereas the reaction mixture clears gradually to become a red solution. After stirring at -78 °C for 30 min, a solution of 5.00 g (13.3 mmol) of the compound of stage 5.2 in THF (10 L) is added at -78 °C within 5 min The resulting reaction mixture is stirred for 1 h and 30 min at -78 °C whereas triphenylphosphine oxide precipitates gradually. Thereupon the reaction mixture is allowed to warm-up at -20 °C and is quenched with saturated aqueous NH4CI (1.10 mL). The beige suspension is partially concentrated under reduced pressure (300 L of distillate). Heptane (100 mL) is added and the suspension is concentrated again under reduced pressure (100 mL of distillate). The resulting residual suspension is filtrated (washing with 50 mL of heptane). The filtrate is collected and concentrated in vacuo. Purification of the residue by flash-chromatography (350 g of Si02, 99:1 to 98:2 gradient hexane/AcOEt) affords the desired vinyl iodide as a colorless oil; Rf = 0.77 (Si02, 9:1 heptane-AcOEt).
Stage 5.1: (2 3S,4S)-3-(terf-Butyl-dimethyl-silanyloxy)-2,4-dimethyl-5-triethylsilanyloxy- pentanoic acid methoxy-methyl-amide
A slightly turbid solution of crude product of stage 3.1 (39.90 g, 125 mmol), imidazole (9.6 g, 141 mmol) and DMAP (1.45 g, 12 mmol) in DMF (110 mL) at 0 °C under an atmosphere of argon is treated dropwise over a period of 20 min with TESCI (19.2 g, 127 mmol). After stirring at 23 °C for 3 h, the reaction mixture is poured into H20 (200 mL). Concentrated HCI (5 mL) is added followed by hexane (250 mL). The layers are separated and the aqu. layer is extracted with hexane (200 mL). The organic extracts are washed with 0.1 N aqu. HCI (150 mL), aqu. sat. NaHC03 (150 mL), combined, dried (MgSO4) and concentrated in vacuo to give the desired bis-silyl ether as a pale yellowish oil which did not require further purification; Rf = 0.39 (Si02, 3:1 hexane-AcOEt).
Stage 5.2: (2R3S.4S)-3-(tert-5tyf -dimethvl-silanvloxv)-2.4-dimethyl-5-triethylsilanvloxv- pentanal
A solution of Red-AI™ (3.5 M in toluene, 13.2 mL, 46 mmol) in toluene (30 mL) at -40 °C under an atmosphere of Ar is treated dropwise over a period 20 min with a solution of the product of stage 5.1 (10.0 g, 23 mmol) in toluene (30 mL). After stirring at -40 °C for 1 h and 15 min, the reaction is quenched by adding dropwise over a period of 15 min aqu. sat. potassium sodium tartrate (50 mL). The resultant mixture is stirred for 3 h at 23 °C. The layers are separated and the aqu. layer is extracted with toluene (30 mL). The organic extracts are washed with aqu. sat. NaHCO3 (50 mL), and H20 (2 x 50 mL), combined, dried (MgSO4) and concentrated in vacuo. The residue is purified by filtration (80g of Si02, 9.5 x 3 cm, elution with 2000 mL of 100:1.5 hexane/AcOEt) to give the desired aldehyde as a colorless oil; Rf = 0.75 (Si02, 3:1 hexane-AcOEt).
Example 6: (2R,3S,4S)-3-(te/t-Butyl-dimethyl-silanyloxy)-2,4-dimethyl-5-triethylsilanyloxy- pentanal
A solution of 0.455 mL (5.30 mmol) of oxalylchloride in 20 mL of CH2CI2 is treated with a solution of 0.75 mL (10.6 mmol) of DMSO in 1.0 mL of CH2CI2 at -78 °C. After 15 min a solution of the compound of stage 6.2 (1.0 g, 2.65 mmol) in 8 mL of CH2CI2 is added dropwise over a period of 30 min. Et3N (2.3 mL, 15.9 mmol) is added over 12 min and the reaction mixture is allowed to warm to RT. After additional stirring for 30 min, 40 mL of TBME and 50 mL of a sat. NH4Cl solution are added. The aqu. layer is separated and extracted twice with 30 mL of TBME. The combined organic layers are washed with 50 mL of brine, dried over MgS0 and concentrated under reduced pressure. The residual oil is purified by flash-chromatography (Si02, 100:1.5 heptane/ethylacetate) to give the desired aldehyde as a colorless oil.
Stage 6.1 : (R)-3-f(2R3S.4S)-3-(tert-Butvl-dimethvl-silanvloxv)-2.4-dimethyl-5-triethvl- silanyIoxy-pentanoyl]-4-isopropyl-5,5-diphenyl-oxazolidin-2-one A solution of the product of stage 1.4 (6.75 g, 12.5 mmol), imidazole (0.96 g, 14.1 mmol), and DMAP (145 mg, 1.2 mmol) in DMF (11.0 mL) at 0 °C under an atmosphere of Ar is treated dropwise over a period of 5 min with TESCI (1.92 g, 12.7 mmol). After stirring at 23 °C for 3 h, the reaction mixture is poured into H20 (20 mL). Concentrated HCI (0.5 mL) is added followed by hexane (25 mL). The layers are separated and the aqu. layer is extracted with hexane (20 mL). The organic extracts are washed with 0.1 N aqueous HCI (15 mL) and sat. aqu. NaHC03 (15 mL), combined, dried (MgS04) and concentrated in vacuo to give the desired bis-silyl etheras a pale yellowish oil which solidified upon storage at 4 °C; Rf = 0.39 (Si02, 3:1 hexane-AcOEt).
Stage 6.2: (2S.3R.4S)-3-(tert-Butvl-dimethvl-silanvloxv)-2.4-dimethvl-5-triethvlsilanvloxv- pentan-1-ol
A 2.0 M solution of LiBH4 (6.55 mL, 13.10 mmol) in THF is added to a solution of the crude product of stage 6.1 (5.36 g, 8.19 mmol) in 130 mL of diethylether and 234 μL (13.02 mmol) of water at 0 °C over a period of 10 min. The mixture is allowed to warm to RT over night. Another 73 μL (4.06 mmol) of water and 2.05 mL (4.09 mmol) of a 2 M LiBH4 solution are added at 23 °C. After additional 6.5 h reaction time further 3 μL (4.06 mmol) of water and 2.05 mL (4.09 mmol) of a 2 M LiBH4 solution are added at 23 °C and the resulting mixture is stirred over night. The reaction is quenched by adding 200 mL of 1 N NaOH followed by the addition of 400 mL of ethylacetate. The phases are separated and the aqu. layer is extracted twice with 150 mL of ethylacetate. The combined organic phases are washed with brine (250 mL), dried over MgS0 and concentrated in vacuo. The residue is suspended in 80 mL of heptane, stirred at 0 °C for 1.5 h and filtered. The obtained cake is washed with cold heptane (75 mL) and dried at 50 °C in vacuo to give recycled auxiliary. The combined filtrates are concentrated to provide the title compound as a colorless oil.
Example 7: (Z)-(5S.6S.7R.8S,9R)-8-(te/ -Butyl-dimethyl-silanyloxy)-10-iodo-5.7.9-trimethyl-6- triethylsilanyloxy-deca-1,3-diene
A solution of the product of stage 7.8 (553 mg, 1.21 mmol) in ether (25 mL) and acetonitrile (7.5 mL) at 0 °C under an atmosphere of Ar is treated with triphenylphosphine (542 mg, 2.07 mmol) and imidazole (124 mg, 1.82 mmol) and the resulting solution is stirred at 0 °C for 15 min. Iodine (460 mg, 1.81 mmol) is added and the suspension is stirred at 0 °C for 1 h. Aqu. Na2S203 (10 % m/m, 10 mL) is added dropwise over a period of 10 min and the resulting colorless two phase mixture is stirred for a further 10 min. TBME (100 mL) is added and the layers are separated. The organic layer is washed with sat. aqu. NaCl (2 x 25 mL), combined, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash- chromatography (60 g of SiO2, 98:2 hexane/AcOEt) afforded the desired alcohol as a pale yellowish oil; Rf = 0.69 (Si02, 9:1 heptane-AcOEt).
Stage 7.1: (2R,3S,4S)-3-(tert-Butyl-dimethyl-silanyloxy)-5-hydroxy-2,4-dimethyl-pentanoic acid methoxy-methyl-amide
A solution of the product of Example 2 (14.21 g) in THF (100 mL) at 23 °C under an atmosphere of Ar is treated with Λ/,0-dimethylhydroxylamine hydrochloride (9.14 g, 94 mmol) and the resulting suspension is cooled at -20 °C. A 2 M solution of isopropylmagnesium chloride in THF (85.5 mL, 171 mmol) is added dropwise over a period of 30 min and the reaction mixture is further stirred at -20 °C for 15 min before it is diluted with TBME (500 mL) followed by addition of 1 :1 v/v mixture of sat. aqu. NH4CI and water (350 mL). The mixture is allowed to warm-up at 23 °C and stirred until the salts are dissolved. The layers are separated and the aqu. layer is extracted with TBME (2 x 250 mL). The organic extracts are washed with sat. aqu. NaCl (2 x 200 mL), combined, dried (MgS0 ) and concentrated in vacuo to give the title compound as a pale yellowish oil; Rf = 0.24 (SiO2, 1:1 heptane- AcOEt).
Stage 7.2: (2R3S,4R)-2,4-Dimethyl-5-oxo-3-triethylsilanyloxy-pentanoic acid methoxy- methyl-amide
A solution of crude product of stage 7.1 (17.79 g) in CH2CI2 (60 mL) at 0 °C under an atmosphere of Ar is treated sequentially with triethylamine (31.0 mL, 223 mmol), DMSO (20 mL) and a solution of sulfur trioxide-pyridine complex (26.6g, 167 mmol) in DMSO (90 mL) which is added dropwise over a period of 30 min. After stirring at 0 °C for 30 min, the reaction mixture is diluted with TBME (500 mL). An aqu. solution of NaHSO (26 g in 250 mL) is added dropwise at 0 °C over a period of 30 min employing a salt-ice cooling bath. The layers are separated and the aqueous layer is extracted with TBME (2 x 250 mL). The organic extracts are washed with aqu. NaHC03 (8% m/m solution, 400 mL) and sat. aqu. NaCl (400 mL), combined, dried (MgS0 ) and concentrated in vacuo to give the title compound as a yellowish oil; Rf = 0.41 (Si02, 1:1 heptane-AcOEt). Stage 7.3: (Z)-(2R3S,4S)-2,4-Dimethyl-3-triethylsilanyloxy-octa-5,7-dienoic acid methoxy- methyl-amide
A suspension of CrCI2 (32.45 g, 265.8 mmol) in THF (200 mL) under an atmosphere of Ar is treated at 0 °C sequentially with a solution of crude product of stage 7.2 (14.07 g, 44.3 mmol) in 60 mL THF and (l-bromo-allyl)-trimethylsilane (34.22 g, 177.2 mmol, rinsed with 10 mL of THF) and the resultant mixture is stirred at 0 °C for 4 h. Phosphate buffer (pH 7, 400 mL, exothermic) is added along with TBME (700 mL). The layers are separated and the aqueous layer is extracted with TBME (2 x 400 mL). The organic extracts are washed with sat. aqu. NaCl (2 x 400 mL), combined, dried (MgS0 ) and concentrated in vacuo to give the crude Nozaki-Hiyama-Kishi intermediate coupling product as a green oil (35.59 g). The crude intermediate dissolved in THF (40 mL) is added dropwise over a period of 25 min to a suspension of KH (1.95 g, 48.6 mmol, from 5.59 g of a 35% suspension of KH in oil) in THF (80 mL) at 0 °C under an atmosphere of Ar. After stirring at 0 °C overnight, the reaction mixture is diluted with hexane (300 mL) and poured into sat. aqu. NH4CI (500 mL) at 0 °C. The pH during the addition is carefully controlled and maintained at a value between 5 and 7 by addition of additional 1 N HCI (33 mL). The layers are then separated and the aqu. layer is extracted with hexane (2 x 300 mL). The organic extracts are washed with sat. aqu. NaCl (2 x 300 mL), combined, dried (MgS0 ) and concentrated in vacuo. The residue is purified by flash-chromatography (450 mL of Si02, 9:1 hexane/AcOEt) to give the desired diene as a pale yellowish oil; Rf = 0.36 (Si02, 3:1 heptane-AcOEt).
Stage 7.4: (Z)-(2R,3S.4S)-2.4-Dimethvl-3-triethvlsilanvloxv-octa-5.7-dienal A solution of the product of stage 7.3 (5.123 g, 15.0 mmol) in THF (14 mL) at -30 °C is treated under an atmosphere of Ar dropwise with a 1.5 molar solution of DIBALH in toluene (10.5 mL, 15.8 mmol). After stirring at -30 °C for 40 min, the reaction is quenched with MeOH (3 mL). Thereafter, sat. aqu. potassium sodium tartrate (200 mL) and hexane (200 mL) are added. The layers are separated and the aqu. layer is extracted with hexane (2 x 100 mL). The organic extracts are washed with sat. aqu. NaHC03 (2 x 100 mL) and sat. aqu. NaCl (100 mL), combined, dried (MgS04) and concentrated in vacuo. The residue is purified by flash-chromatography (400 mL of Si02, 19:1 hexane/AcOEt) to give the desired aldehyde as a colorless oil; Rf = 0.61 (Si02, 3:1 heptane-AcOEt).
Stage 7.5: (R)-3-f(Z)-(2R,3S.4S.55,6S)-3-Hvdroxy-2,4,6-trimethvl-5-triethvlsilanvloxv-deca- 7,9-dienoyl]-4-isopropyl-5,5-diphenyl-oxazolidin-2-one A solution of (R)-4-isopropyl-5,5-diphenyl-3-propionyl-oxazolidin-2-one (961 mg, 2.85 mmol) in CH2CI2 (3.0 mL) at 0 °C under an atmosphere of Ar is treated sequentially with n-Bu2BOTf (1 M in CH2CI2, 2.70 mL, 2.70 mmol) and triethylamine (0.50 mL, 3.47 mmol). After stirring at 0 °C for 1 h, the resulting solution is cooled to -78 °C and treated with a solution of the product of stage 7.4 (565 g, 2.00 mmol) in CH2CI2 (2.0 mL). The reaction solution is stirred successively at - 78 °C for 15 min and at 0 °C for 30 min. Phosphate buffer (pH 7, 3.0 mL), MeOH (9.0 mL) and MeOH/35% H202 (6:1 v/v, 3.5 mL) are added sequentially at 0 °C. After stirring for 1 h at 0 °C, the resulting two phase mixture is treated with 40% aqu. Na2S203 (3.0 mL). The volatiles are removed in vacuo and the residual aqu. phase is diluted with H20 (20 mL) and extracted with AcOEt (2 x 20 mL). The combined organic layers are washed with sat. aqu. NaHCO3 (10 mL) and sat. aqu. NaCl (10 mL), dried over MgS04, filtered, and concentrated in vacuo. Purification of the residue by flash-chromatography (250 g of SiO2, 9:1 hexane/AcOEt) afforded the desired aldol product as a waxy solid contaminated by (R)- 4-isopropyl-5,5-diphenyl-3-propionyl-oxazolidin-2-one; Rf = 0.46 (Si02, 3:1 heptane-AcOEt).
Stage 7.6: (R)-3-r(Z)-(2R3S,4R5S,6S)-3-(tert-Butvl-dimethvl-silanvloxv)-2.4,6-trimethvl-5- triethylsilanyIoxy-deca-7,9-dienoyl]-4-isopropyl-5,5-diphenyl-oxazolidin-2-one A solution of the product of stage 7.5 (1.06 g, 1.71 mmol) and 2,6-lutidine (0.515 mL, 4.44 mmol) in CH2CI2 (8 mL) at -20 °C under an atmosphere of Ar is treated dropwise with TBDMSOTf (0.915 mL, 4.00 mmol). The resulting reaction mixture is allowed to warm-up at 0 °C within 30 min and stirred for an additional 2 h and 30 min. TBME (25 mL) and 1N HCI (15 mL) are added sequentially and the layers are separated. The aqu. layer is extracted with TBME (25 mL). The organic layers are washed with 1N HCI (15 mL), sat. aqu. NaHCO3 (15 mL) and sat. aqu. NaCl (15 mL), combined, dried over MgS04 and concentrated in vacuo. Purification of the residue by flash-chromatography (200 g of Si02, 95:5 hexane/ AcOEt) afforded the title compound as a colorless oil; Rf = 0.56 (Si02, 3:1 heptane-AcOEt).
Stage 7.7: (Z)-(2R,3S,4R5S,6S)-3-(terf-Butvl-dimethvl-silanvloxv)-2.4,6-trimethvl-5- triethylsilanyloxy-deca-7,9-dienethioic acid S-benzyl ester
The title compound is obtained from the product of stage 7.6 in analogy to Example 8 (see below); Rf = 0.77 (Si02, 9:1 heptane-AcOEt). Stage 7.8: (Z)-(2S.3R4R5S.6S)-3-fferf-Butvl-dimethvl-silanvloxv)-2.4.6-trimethvl-5- triethylsilanyloxy-deca-7,9-dien-1-ol
LiBH4 (300 mg 14 mmol), and EtOH (0.80 mL, 14 mmol) are added sequentially to a solution of crude product of stage 7.7 (1.28 g) in THF (20 mL) at 0 °C under an atmosphere of Ar. The resulting mixture is stirred at 23 °C overnight for 17 h. NaOH 1 N (30 mL) is added. After stirring for 1 h at 23 °C, TBME (40 mL) is added and the layers are separated. The aqu. layer is extracted with TBME (2 x 40 mL). The organic layer is washed with 1 N NaOH (30 mL), and sat. aqu. NaCl (2 x 40 mL), combined, dried over MgS04 and concentrated in vacuo. Purification of the residue by flash-chromatography (200 g of Si02, 95:5 hexane/ AcOEt) afforded the desired alcohol as a pale yellowish oil; Rf = 0.56 (Si02, 3:1 heptane- AcOEt).
Example 8: (Z)-(2R3S,4R5S,6S)-3-(tert-Butyl-dimethyl-silanyloxy)-2.4.6-trimethvi-5- triethylsilanyloxy-deca-7.9-dienethioic acid S-benzyl ester
A solution of benzyl mercaptan (0.80 mL, 6.8 mmol) in THF (20 mL) at 0 °C under an atmosphere of argon is treated dropwise over a period of 15 min with n-BuLi (1.6 M in hexanes, 3.12 mL, 5.0 mmol). After stirring at 0 °C for 15 min, a solution of the product of stage 8.2 (1.10 g, 1.75 mmol) in THF (10 mL) is added dropwise. The reaction mixture is stirred at 0 °C for 1 h. 1N NaOH (40 mL) and TBME (40 mL) are added sequentially and the layers are separated. The organic layer is washed with 1N NaOH (40 mL), and sat. aqu. NaCl (2 x 40 mL), combined, dried over MgS04 and concentrated in vacuo to give the crude thioester as a gel. An analytical sample is obtained by purification with flash-chromatography (Si02, 95:5 hexane/AcOEt); Rf = 0.77 (SiO2, 9:1 heptane-AcOEt).
Stage 8.1 : (R)-4-Benzvl-3-r(Z)-(2R3S.4S.5S,6S)-3-hvdroxv-2.4.6-trimethvl-5-triethvlsilanvl- oxy-deca-7,9-dienoyl]-oxazolidin-2-one
A solution of (R)-4-benzyl-3-propionyloxazolidin-2-one (1.33 g, 5.70 mmol) in CH2CI2 (6.0 mL) at 0 °C under an atmosphere of argon is treated sequentially with n-Bu2BOTf (1 M in CH2CI2, 5.40 mL, 5.40 mmol) and triethylamine (1.00 mL, 7.17 mmol). After stirring at 0 °C for 1 hr, the resulting yellow solution is cooled to -78 °C and treated with a solution of the product of stage 7.4 (1.13 g, 4.00 mmol) in CH2CI2 (4.0 mL). The reaction solution is stirred successively at - 78 °C for 15 min and at 0 °C for 30 min. Phosphate buffer (pH 7, 6.0 mL), MeOH (9.0 mL) and MeOH/35% H202 (6:1 v/v, 7.0 mL) are then added sequentially at 0 °C. After stirring for 1 h at 0 °C, the resulting two phase mixture is treated with 40% aqu. Na2S203 (6.0 mL). The volatiles are removed in vacuo and the residual aqu. phase is diluted with H20 (20 mL) and extracted with AcOEt (2 x 40 mL). The combined organic layers are washed with sat. aqu. NaHC03 (20 mL) and sat. aqu. NaCl (20 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash-chromatography (200 g of Si02, 9:1 hexane/AcOEt) afforded the desired aldol product as a colorless oil; Rf = 0.29 (SiO2, 3:1 heptane-AcOEt).
Stage 8.2: (R)-4-Benzvl-3-r(Z)-(2R.3S.4R.5S,6S)-3-(terf-butvl-dimethvl-silanvloxv)-2.4.6- trimethyl-5-triethylsilanyloxy-deca-7,9-dienoyl]-oxazolidin-2-one
A solution of the product of stage 8.1 (1.74 g, 3.37 mmol) and 2,6-lutidine (1.03 mL, 8.87 mmol) in CH2CI2 (16 mL) at -20 °C under an atmosphere of Ar is treated dropwise with TBDMSOTf (1.83 mL, 8.00 mmol). The resulting reaction mixture is allowed to warm-up at 0 °C and is stirred for an additional 2 h and 30 min. TBME (50 mL) and 1 HCI (30 mL) are added sequentially and the layers are separated. The aqueous layer is extracted with TBME (50 mL). The organic layers are washed with 1 HCI (30 mL), sat. aqu. NaHCO3 (30 mL) and sat. aqu. NaCl (30 mL), combined, dried over MgS04 and concentrated in vacuo. Purification of the residue by flash-chromatography (200 g of Si02, 95:5 hexane/AcOEt) afforded the desired silyl-ether product as a colorless oil; Rf = 0.52 (Si02, 3:1 heptane- AcOEt).
Example 9: (Z)-(2R.3S.4S)-2.4-Dimethyl-3-triethylsiIanyloxy-octa-5.7-dienal
A solution of 0.455 mL (5.30 mmol) of oxalylchloride in 20 mL of CH2CI2 is treated with a solution of 0.75 mL (10.6 mmol) of DMSO in 1.0 mL of CH2CI2 at -78 °C. After 15 min a solution of the product of stage 9.3 (750 mg, 2.64 mmol) in 8 mL of CH2CI2 is added dropwise over a period of 30 min. Et3N (2.3 mL, 15.9 mmol) is added over 12 min and the reaction mixture is allowed to warm to RT. After additional stirring for 30 min, 40 mL of TBME and 50 mL of a sat. NH4CI solution are added. The aqu. layer is separated and extracted twice with 30 mL of TBME. The combined organic layers are washed with 50 mL of brine, dried over MgS04 and concentrated under reduced pressure. The residual oil was purified by flash-chromatography (SiO2, 98:2 heptane/ethylacetate) to give the desired aldehyde as a colorless oil. Stage 9.1 : (2R3S.4R)-5-r(R)-4-lsopropvl-2-oxo-5.5-diphenvl-oxazolidin-3-vll-2.4-dimethvl-5- oxo-3-triethylsilanyloxy-pentanal
A solution of the produzct of stage 2.2 (1.72 g, 3.19 mmol) in CH2CI2 (8 mL) at 0 °C under an atmosphere of Ar is treated sequentially with triethylamine (1.78 mL, 12.8 mmol), DMSO (1.13 mL) and a solution of sulfur trioxide-pyridine complex (1.52g, 9.6 mmol) in DMSO (5.2 mL) which is added dropwise over a period of 15 min. After stirring at 0 °C for 3 h, the reaction mixture is diluted with TBME (20 mL). A mixture of aqu. NaHS04 (1 M, 12.5 mL) and H20 (3.1 mL) is added dropwise over a period of 10 min and the layers are separated. The aqu. layer is extracted with TBME (20 mL). The organic extracts are washed with aqu. NaHC03 (8% m/m, 20 mL) and sat. aqu. NaCl (2 x 25 mL), combined, dried (MgS04) and concentrated in vacuo. The residue is purified by flash-chromatography (30 g of Si02, 95:5 heptane/AcOEt) to give the title compound as a white foam.
Stage 9.2: (R)-3-r(Z)-(2R3S,4S)-2,4-Dimethvl-3-triethvlsilanvloxv-octa-5.7-dienovll-4- isopropyl-5,5-diphenyl-oxazolidin-2-one
A green-colored suspension of CrCI2 (3.24 g, 26.6 mmol) in THF (20 mL) at 0 °C under an atmosphere of Ar is treated sequentially with a solution of the product of stage 9.1 (2.38 g, 4.43 mmol) in THF (6 mL) and (l-bromo-allyl)-trimethylsilane (3.42 g, 17.7 mmol, rinsed with 2 mL of THF) and the resultant mixture is stirred at 0 °C for 4 h. The reaction is then worked- up by addition of phosphate buffer (pH 7, 40 mL, exothermic) along with TBME (70 mL). The layers are separated and the aqu. layer is extracted with TBME (2 x 40 mL). The organic extracts are washed with sat. aqu. NaCl (2 x 40 mL), combined, dried (MgS04) and concentrated in vacuo to give the crude Nozaki-Hiyama-Kishi intermediate coupling product as a green oil. The crude intermediate dissolved in THF (10 mL) was added dropwise over a period of 5 min to a suspension of KH (195 mg, 48.6 mmol, from 560 mg of a 35% suspension of KH in oil) in THF (8 mL) at 0 °C under an atmosphere of Ar. After stirring at 0 °C overnight, the reaction mixture is diluted with hexane (30 mL) and poured into sat. aqu. NH4CI (50 mL) at 0 °C. The pH during the addition is carefully controlled and maintained at a value between 5 and 7 by addition of additional 1 N HCI (3.3 mL). The layers are separated and the aqu. layer is extracted with hexane (2 x 30 mL). The organic extracts are washed with sat. aqu. NaCl (2 x 30 mL), combined, dried (MgS04) and concentrated in vacuo. The residue is purified by flash-chromatography (45 mL of Si02, 95:5 hexane/AcOEt) to give the desired diene as a pale yellowish oil. Stage 9.3: (Z)-(2S,3S.4S)-2,4-Dimethvl-3-triethylsilanvloxv-octa-5,7-dien-1 -ol A 2.0 M solution of LiBH4 (6.55 mL, 13.10 mmol) in THF is added to the product of stage 9.2 (4.60 g, 8.19 mmol) in 130 mL of diethylether and 234 μL (13.02 mmol) of water at 0 °C over a period of 10 min. The mixture is allowed to warm to RT over night. The cleaved chiral auxiliary formed a white crystalline precipitate. Another 73 μL (4.06 mmol) of water and 2.05 mL (4.09 mmol) of a 2 M LiBH4 solution are added at 23 °C. After additional 6.5 h reaction time further 73 μL (4.06 mmol) of water and 2.05 mL (4.09 mmol) of a 2 M LiBH4 solution are added at 23 °C and the resulting mixture is stirred over night. The reaction is quenched by adding 200 mL of 1 NaOH followed by 400 mL of ethylacetate. The phases are separated and the aqu. layer is extracted twice with 150 mL of ethylacetate. The combined organic phases are washed with brine (250 mL), dried over MgS04 and concentrated in vacuo. The residue is suspended in 80 mL of heptane and stirred at 0 °C for 1.5 h and filtered. The resulting cake is washed with cold heptane (75 mL) and dried at 50 °C in vacuo to give 1.49 g (65 %) of recycled auxiliary. The combined filtrates are concentrated to provide the title compound as a colorless oil.
Example 10: (3Z.11Z)-(5S,6S.7S,8R9S.13S.14R15S)-8.14-Bis-(fert-butyl-dimethyl- silanyloxy)-5.7.9.11.13.15-hexamethyl-6.16-bis-triethylsilanyloxy-hexadeca-1.3.11-triene
A dried reactor (50 mL) equipped with a magnetic stirring bar and under an atmosphere of argon is charged sequentially with n-hexane (3.7 mL) and a solution of f-BuLi in pentane (3.50 L, 6.02 mmol, 1.7 M). The resulting solution is cooled to -78 °C. A solution of the product of Example 7 (1.59 g, 2.80 mmol) in Et20 (16.8 mL) is added within 5 min so that the internal temperature of the reaction mixture does not exceed -75 °C. At the end of the addition, the reaction mixture is stirred at -78 °C for no longer than 10 min. Pure β-methoxy- 9-BBN (553 mg, 3.64 mmol) is added to the yellow turbid solution within 5 minutes so that the internal temperature of the reaction mixture does not exceed -75 °C. At the end of the addition, the reaction mixture is stirred at -78 °C for no longer than 10 min. THF (16.8 mL) is added within 10 min so that the internal temperature of the reaction mixture does not exceed -75 °C. At the end of the addition, the resulting white suspension is stirred at -78 °C for 10 min and is allowed to return to 23 °C within 1.5 h. While the borane solution is warming up, a solution of the product of Example 5 (1.03 g, 2.00 mmol) in DMF ( 20 mL) is added under an atmosphere of argon. To the solution at 23 °C, Cs2C03 (2.53 g, 7.76 mmol) dissolved in water (2.15 mL) was added. The catalyst [Pd(dppf)CI2.CH2CI2] (82 mg, 0.10 mmol, 5 mol%) is added as a solid in one portion. The borane solution derived from the product of Example 7 [ca 42 mL) transferred into a dropping funnel is then added to the Example 5-base-catalyst solution at 23 °C over a period of 30 min. The reaction mixture is stirred at 23 °C over night. The heterogeneous reaction mixture (ca 68 mL) is filtrated over a pad of cellflock before being extracted with heptane (2 x 50 mL). The heptane fractions are back-extracted with a 1:1 v/v mixture of aqu. sat. NaCl and water (2 x 30 mL) before being combined and dried over MgS04. The heptane fraction is concentrated in vacuo at 40 °C to 12 L. To the resulting turbid brown solution containing a dark-brownish precipitate ethanolamine (245 mg, 4.00 mmol, 1.1 eq. per eq. β-methoxy-9-BBN utilized) is added. The resulting mixture is stirred for 1 h at 23 °C before being treated with Celite and filtrated over a filter coated with Celite (5 g). The filtercake is rinsed with heptane (3 x 5 mL) and the filtrate is concentrated in vacuo at 40 °C to 3 g. The clear yellowish solution is transferred over a short column of Si02 and filtrated. HeptaneTBME 95:5 v/v (130 mL) is utilized for the elution. The organic solvents are removed in vacuo at 40 °C and the yellowish oil residue is dried at 23 °C in vacuo (1 mbar) over night. Purification of the residue by flash-chromatography (45 mL of Si02, hexane) affords the desired coupling product as a pale yellowish oil; Rf = 0.77 (Si02, 9:1 hexane-AcOEt).
Example 11: Carbamic acid (6Z.11ZH1S,2R3R4S,8S,9S.10S)-3,9-bis-(te/f-butyl-dimethyl- silanyloxy)-2.4, 6.8.10-pentamethyl-1-( (Z)-(S)-1 -methyl-penta-2,4-dienyl)-13-oxo-tetradeca- 6.11-dienyl ester
To a solution of the product of stage 11.3 (178 mg, 0.28 mmol) in CH2CI2 (5 mL) is added CI3CONCO (100 μL, 0.84 mmol). After 20 min stirring at RT, 2.0 g of neutral alumina (oven dried) is added. The suspension is stirred at RT for 4 h, concentrated under reduced pressure and purified by flash-chromatography (25 g of Si02, heptane/AcOEt 9:1) to provide the desired carbamate as a colorless oil.
Stage 11.1: (3Z, 11 Z)-(5S,6S,7S,8R,9S, 13S, 14R,15S)-8, 14-Bis-(ferf-butyl-dimethyl-silanyl- oxyJ-δJ.Θ.II.IS.Iδ-hexamethyl-β.ie-bis-triethylsilanyloxy-hexadeca-I.S.II-triene
To a solution of the product of Example 10 (2.06 g, 2.50 mmol) in THF/CH3OH/H20 5:5:1 v/v/v (25 mL) at 23 °C is added chloroacetic acid (2.36 g, 25.0 mol). The resulting reaction solution is heated at 50 °C for 5 h. The reaction mixture is quenched with H2O (25 mL) and extracted with TBME (2 x 40 mL). The organic extracts are washed with aqu. sat. NaHCO3 (40 mL) and aqu. sat. NaCl (40 mL), combined, dried (MgSO4) and partially concentrated under reduced pressure. Purification of the residue by flash-chromatography (200 g of Si02l hexane/AcOEt 3:1) affords the desired diolas a pale yellowish oil.
Stage 11.2: (5Z,13Z)-(2R.3R4S,8S.9R,10R11S.12S)-3.9-Bis-(ten'-butvl-dimethvl-silanvl- oxy)-11-hydroxy-2,4,6,8,10,12-hexamethyl-hexadeca-5,13,15-trienal A solution of the product of stage 11.1 (20.0 g, 33.5 mmol) in CH2CI2 (100 mL) at 0 °C under an atmosphere of argon is treated sequentially with TEMPO (1.05 g, 6.7 mmol) and iodobenzene diacetate (32.4 g, 100.9 mmol). The resulting orange suspension is stirred at RT for 3 h after which a 3:1 v/v mixture of 5% aqu. Na2S203 and 30% aqu. Na2S203 (400 mL) is added dropwise followed by TBME (400 mL). The layers are separated and the aqu. layer is extracted with TBME (150 mL). The organic extracts are washed with 8% aqu. NaHC03 (200 mL) and aqu. sat. NaCl (300 mL), combined, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash-chromatography (1150 g of Si02, heptane/AcOEt 90:7) affords the desired aldehyde as a pale yellowish oil; Rf = 0.56 (Si02, 4:1 heptane-AcOEt).
Stage 11.3: (3Z,8Z, 16Z)-(5S,6S,7S, 11 S, 12R, 13R, 14S, 15S)-6, 12-Bis-(ferf-butyl-dimethyl- silanyloxy)-14-hydroxy-5,7,9,11 , 13,15-hexamethyl-nonadeca-3,8,16,18-tetraen-2-one A suspension of anhydrous micronized K2C03 (1.70 g, 12.3 mmol) and 18-crown-6 (6.55 g, 24.8 mmol) in a 45:5 v/v mixture of toluene and HMPA (27.3 mL) is stirred for 2 h and 45 min at ambient temperature before being cooled at -15 °C and treated dropwise within 10 min with a solution of the product of stage 11.2 (1.23 g, 2.07 mmol) and (2-oxo-propyl)- phosphonic acid bis- (2,2,2-trifluoro-ethyI) ester (2.50 g, 8.27 mmol) in a 45:5 v/v mixture of toluene and HMPA (27.3 mL). The resulting cloudy yellowish reaction mixture is stirred successively at -15 °C for 3 h and 20 min and at 0 °C for 15 h. aqu. sat. NH4CI (10 mL) and TBME (50 mL) are added sequentially. The layers are separated and the aqu. layer is extracted with TBME (20 mL). The organic extracts are washed with aqu. sat. NaCl (3 x 30 mL) and H2O (30 mL), combined, dried over MgS0 and concentrated in vacuo. Purification of the residue by flash-chromatography (150 g of SiO2, heptane/AcOEt 95:5) affords the desired triene as a colorless oil. Example 12: (8Z.13Z.21Z -(2R3S.4S.5S.10S.11S.12S.16S.17R18S.19S.20S)-3.11.17-Tris- (terf-butyl-dimethyl-silanyloxy)-19-carbamoyloxy-5-hvdroxy-2.4.10.12.14.16.18,20- octamethyl-7-oxo-tetracosa-8, 13.21.23-tetraenoic acid methoxy-methyl-amide
To a solution of the product from Example 11 (419 mg, 0.66 mmol) in Et20 (5.0 mL) at 0 °C under an atmosphere of argon is added cHeXjBCI (440 μl, 1.98 mmol) and immediately afterwards triethylamine (310 μl, 2.17 mmol). After 30 min at 0 °C, the reaction mixture is cooled to -78 °C. A solution of the product of Example 3 (629 mg, 1.98 mmol) in Et20 (15 mL) is added dropwise. The reaction mixture is stirred at -78 °C for 20 h before being allowed to warm up to 0 °C and is quenched by the addition of pH 7 phosphate buffer (20 mL). The aqueous layer is extracted with TBME (2 x 30 mL). The organic extracts are washed with sat. aqu. NaHC03 (30 mL) and brine (30 mL), combined, dried (MgS04) and concentrated in vacuo. The residue was purified by flash-chromatography (100 g of Si02, 95:5 to 90: gradient 10 heptane/AcOEt) to give the desired aldol product as a colorless foam; Rf = 0.45 (Si02, 7:3 heptane-AcOEt).
Example 13: (R)-4-lsopropyl-5,5-diphenyl-3-f(8Z.13Z.21Z)-(2R3S.4S.5S.10S.11S.12S, 16S.17R18S.19S.20S)-3.11.17-tris-fterf-butyl-dimethyl-silanyloxy)-19-carbamoyloxy-5- hvdroxy-2.4.10.12.14.16.18.20-octamethyl-7-oxo-tetracosa-8.13.21.23-tetraenovn- oxazolidin-2-one
To a solution of the product from Example 11 (419 mg, 0.66 mmol) in Et20 (5.0 mL) at 0 °C under an atmosphere of argon is added cHex^Cl (440 μl, 1.98 mmol) and immediately afterwards triethylamine (310 μl, 2.17 mmol). After 30 min at 0 °C, the reaction mixture is cooled to -78 °C. A solution of the product of Example 4 (1065 mg, 1.98 mmol) in EtzO (15 mL) is added dropwise. The reaction mixture is stirred at -78 °C for 20 h before being allowed to warm up to 0 °C and is quenched with pH7 phosphate buffer (20 mL). The aqueous layer is extracted with TBME (2 x 30 mL). The organic extracts are washed with sat. aqu. NaHC03 (30 mL) and brine (30 mL), combined, dried (MgS04) and concentrated in vacuo. The residue is purified by flash-chromatography (100 g of Si02, 95:5 heptane/AcOEt) to give the desired aldol product as a colorless foam.
Example 14: (ZH2S, 3S. 4S)-3-(p-Methoxybenzyloxy)-2,4-dimethyl-octa-5,7-dienal To a stirred solution of alcohol of stage 14.9 (428 mg, 1.48 mmol) in CH2CI2 (5 mL) at RT is added Dess-Martin periodinane (900 mg, 2.12 mmol). After 15 min, hexane (5 mL) is added and the resultant suspension is purified directly by flash chromatography (5% EtOAc/ Hexanes) to afford the title compound as a colourless oil; Rf 0.23 (10 % EtOAc/hexane); IR
(Thin film) 2964 (s), 2872 (s), 1721 (s), 1613 (s), 1514 (s); 1H NMR (400 MHz, CDCI3) dH 9.69 (1H, d, J = 1.2 Hz, H-|), 7.22 (2H, d, J = 8.7 Hz, ArH), 6.85 (2H, d, J = 8.7 Hz, ArH), 6.55 (1H, dddd, J = 16.8, 10.7, 10.4, 0.9 Hz, H7), 6.04 (1H, dd, J = 11.0, 11.0 Hz, He), 5.44 (1H, dd, J = 10.6, 10.4 Hz, H5), 5.21 (1H, d, J = 16.8 Hz, HSA). 5.11 (1H, d, J = 10.1 Hz, H8B). 4.50 (1H, d, J = 10.8 Hz, ^HeAr), 4.44 (1H, d, J = 10.8 Hz, CHAHβAr), 3.79 (3H, s, OCH3), 3.70 (1H, dd, J = 5.1, 5.1 Hz, H3), 3.00-2.90 (1H, m, H4), 2.59 (1H, qdd, J= 7.0,
5.0, 1.2 Hz, H2), 1.15 (3H, d, J = 6.9 Hz, Me4), 1.05 (3H, d, J = 7.0 Hz, Me2); HRMS (ES+) calcd for C-|δH24θ3Na [M+Na]+ 311.1623. Found 311.1631.
Stage 14.1: Methyl (S)-3-(p-MethoxybenzyIoxy)-2-methyipropionate To a stirred solution of (6.6 g, 55.8 mmol, 1.0 eq.) methyl (S)-3-hydroxy-2-methylpropionate and p-methoxybenzyltrichloroacetimidate (18.9 g, 66.9 mmol, 1.2 eq.) in Et2θ (400 mL) at 0°C, a solution of triflic acid in Et2θ (1.5 mL of a 0.45 M solution, 0.67 mmol) is added. The reaction mixture is stirred at 0°C for 40 min, then at RT for 20 min, before being quenched with aqu. NaHC03 (300 mL). The aqu. layer is extracted with Et2θ (4 x 100 mL), the combined organic layers are dried (MgSO4) and concentrated in vacuo. The solid crude is triturated with cold hexane (300 mL) and the filtrate is concentrated in vacuo to yield the crude protected ester. Purification by flash chromatography on silica gel (10% Et2θ / PE) gives the title compound as a colourless oil; Rf 0.25 (17% EtOAc / Hexane).
Stage 14.2: (S)-Λ/-Methoxy-Λ/,2-dimethyl-3-(p-Methoxybenzyloxy)propanamide To a stirred mixture of 7.03 g (29.53 mmol, 1.0 eq.) of the ester of stage 14.1 and N,0- dimethyl hydroxylamine hydrochloride (4.36 g, 44.68 mmol, 1.5 eq.) in THF (400 mL) at -30°C is added isoPrMgCI (44.7 mL of a 2M solution in THF, 89.37 mmol, 3.0 eq.) dropwise, maintaining the reaction temperature below -20 °C at all times. After 45 min at this temperature, aqu. NH4CI (200 mL) is added, and the aqu. layer is extracted with Et2θ (3 x 100 mL). The combined organic layers are concentrated in vacuo and the product is purified by flash chromatography on silica gel (20% to 50% EtOAc / PE), to yield the desired Weinreb amide as a colourless oil; Rf 0.27 (50% EtOAc / Hexane); 3C NMR (62 MHz, CDCI3) δc 175.8, 159.0, 130.4, 129.0 (2C), 113.6 (2C), 72.8, 72.2, 61.4, 55.1, 35.8, 32.1, 14.1.
Stage 14.3: (S)-1-(p-Methoxybenzyloxy)-2-methylpentan-3-one (13) To a stirred solution of 4.22 g (15.8 mmol) of the Weinreb amide of stage 14.2 in THF (200 mL) at -30°C is added EtMgCI (11.9 L of a 2M solution in Et2θ, 23.7 mmol, 2.0 eq.) dropwise. The reaction mixture is stirred for 2.5 h, allowing the temperature to reach 5°C. It is then carefully quenched with aqu. NH4CI (100 mL). The aqu. layer is extracted with Et2θ (4 x 100 mL). The combined organic extracts are washed with brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography on silica gel (10% Et20 / PE) gives the title compound as a colourless oil; Rf 0.34 (20% EtOAc / Hexane); 13C NMR (62 MHz, CDCI3) δc 213.5, 159.1, 130.2, 129.1 (2C), 113.7 (2C), 72.8, 72.0, 55.1, 46.1, 35.1, 13.5, 7.4.
Stage 14.4: (2S, 4S)-1 -Hydroxy-5-(p-methoxybenzyloxy)-2,4-dimethylpentan-3-one Dicyclohexylboron chloride (6.17 mL, 28.15 mmol, 1.3 eq) is dissolved in Et2θ (80 mL), and the resulting mixture is cooled to 0°C before the addition of Etβ (4.83 mL, 34.6 mmol, 1.6 eq.). The ethyl ketone of stage 14.3 (5.11 g, 21.6 mmol, 1.0 eq.) is added via cannula as an Et2θ solution (15 mL) and the mixture is stirred at 0°C for 2 hours. A freshly prepared formaldehyde solution is added to the reaction mixture via cannula. After 1 hour at -78°C the reaction mixture is allowed to warm to 0°C before the addition of MeOH (80 mL) and pH 7 buffer (80 mL). Hydrogen peroxide (30 mL, 30% aqueous) is added dropwise at 0°C. After 1 h at RT, the mixture is extracted with dichloromethane (3 x 200 mL). The combined extracts are dried (MgSO4) and concentrated in vacuo. Flash chromatography (15% EtOAc / Hexane) provides the desired aldol adduct as a colourless oil; Rf 0.43 (50% EtOAc / Hexane); IR (Thin Film) 3448 (s br, OH), 2970 (s), 2935 (s), 2875 (s), 1709 (s, C=0), 1613 (m), 1586 (w), 1514 (s), 1462 ( ); m/z (Cl+) 284 (1, [M+NH4]+), 138 (12), 121 (100).
Stage 14.5: (2S, 3R 4S)-5-(p-Methoxybenzyloxy)-2,4-dimethylpentane-1,3-diol Sodium triacetoxyborohydride (6.35 g, 29.98 mmol, 4.0 eq.) is carefully dried in vacuo before the addition of THF (100 mL). The slurry is cooled to 0°C and the β-hydroxyketone of stage 14.3 (1.99 g, 7.49 mmol, 1.0 eq) dissolved in THF (50 mL) is added via cannula. Acetic acid (5 mL) is added dropwise and the mixture is stirred at 0°C for 30 min and then at RT for 20 h. K/Na tartrate (150 mL, saturated aqu. solution) is added and stirring continued for 2 h until both layers are clear. The biphasic solution is partitioned between sat. aqu. NaHC03 (200 mL) and dichloromethane (150 mL), and the aqu. layer extracted with dichloromethane (3 x 100 mL). The combined organic extracts are dried over MgSθ4 and concentrated in vacuo to give a 9 : 1 crude diastereomeric mixture. White crystalline diol title compound is obtained by recrystallisation in a 50% mixture of PE in Et2θ; Rf 0.25 (50% EtOAc / Hexane); m/z (Cl+) 269 (28, [M+H]+), 149 (45), 138 (27), 121 (100).
Stage 14.9: (Z)-(2S, 3S, 4S)-3-(p-Methoxybenzyloxy)-2,4-dimethyl-octa-5,7-dien-1-ol To a stirred solution of crude TBS ether of stage 14.8 (3.00 g, 6.6 mmol) in CH2CI2 (40 mL) and MeOH (20 mL) at RT is added CSA (306 mg, 1.32 mmol). After 4 hr the reaction is partitioned between NaHCθ3 (20 mL) and CH2CI2 (3 x 50 mL). The combined organic layers are dried (MgSθ4), concentrated in vacuo and purified by flash chromatography (15- 35% EtOAc/Hexanes) to provide the title compound as a colourless oil; Rf 0.29 (40% EtOAc/Hexane).
Example 15: (2R 3S. 4S)-2.4-dimethyl-3-hvdroxy-5-(4-methoxybenzyloxy)pentanal
To a stirred solution of the diol of stage 14.5 (500 mg, 1.866 mmol) in dichloromethane (5 ml) at RT bis-acetoxyiodobenzene (332 mg, 1.03 mmol) and TEMPO (27 mg, 0.17 mmol) are added. The solution is stirred for 5 h before addition of sat. aqu. Na2S2θ3 solution (10 mL). The biphasic mixture is vigorously stirred for 20 min. Extraction with dichloromethane (4 x 10 mL), washing with aqu. NaHCθ3, drying (Na2Sθ4) and evaporation of solvents yields the desired aldehyde, which can be used without further purification; Rf:0.23 (33% EtOAc / hexane); 1H NMR (250 MHz, CDCI3) δH 9.72 (1H, s, Hi), 7.24 (2H, d, J = 8.6 Hz, PMB), 6.88 (2H, d, J = 8.7 Hz, PMB), 4.46 (2H, s, PMB), 4.08 (1H, dd, J = 8.8, 2.9 Hz, H3), 3.8 (4H, s, OMe + OH), 3.62 (1H, dd, J = 9.2, 4.0 Hz, H5A), 3.50 (1H, dd, J = 9.0, 8.4 Hz, H5B), 2.42 (1H, dq, J = 7.0, 2.6 Hz, H2), 2.0 (1H, m, H ), 1.14 (3H, d, J = 7.0 Hz, Me2), 0.84 (3H, d, J = 7.0 Hz, Me4). Example 16: (2R 3R 4S, 5Z. 8S. 9R 10S. 11S. 12S. 13Z)-3,9-Bis-(r-butyldimethylsilyloxy)- 11-hvdroxy-2.4,6.8.10.12-hexamethyl-hexadeca-5,13,15-trienal
Figure imgf000072_0001
To a stirred solution of diol of stage 16.6 (115 mg, 0.193 mmol) in CH2CI2 (0.5 mL) at RT is added TEMPO (6 mg, 0.039 mmol), followed by iodobenzene diacetate (186 mg, 0.579 mmol). After 2 h the reaction mixture is partitioned between NaS2U3 (3 mL) and CH2CI2 (3 x 10 mL). The combined organic extracts are washed NaHC03 (15 mL), dried (MgSθ4) and concentrated in vacuo. Flash chromatography (10% EtOAc/Hexanes) gives the desired aldehyde as a colourless oil; Rf 0.35 (25% EtOAc/Hexane); [of +29.7 (c 5.3, CHCI3); IR
(Thin film) 3473 (m br, OH), 2958 (s), 2857 (s), 1724 (s, C=O), 1463 (s), 1376 (s); 1H NMR (500 MHz, CDCI3) δH 9.65 (1H, s, Hg), 6.66 (1H, ddd, J = 16.9, 10.6, 10.5 Hz, H23), 6.17 (1 H, dd, J = 10.9, 10.9 Hz, H22). 5.37 (1 H, dd, J = 10.4, 10.3 Hz, H21 ), 5.27 (1 H, d, J = 16.8 Hz, H24A). 5.19 (1H, d, J = 10.1 Hz, H13), 4.86 (1H, d, J = 10.4 Hz, H24B)> 3.78 (1H, dd, J = 7.7, 3.2 Hz, H11), 3.64 (1H, app br s, H17), 3.38 (1H, app d, J = 4.2 Hz, H19), 2.90-2.79 (1H, m, H20), 2.64-2.47 (2H, m, H10 + H-|2), 2.20 (1H, dd, J = 12.2, 12.2 Hz, Hι5A), 1.95-1.87 (1H, m, H16), 1.87-1.80 (1H, m, H<|8), 1.78 (1H, app d, J = 12.6 Hz, Hι5B), 1.61 (3H, s, Me ), 1.10 (3H, d, J = 6.9 Hz, Me10), 1.04-0.97 (9H, m, Me-|2 + Me-|8 + Me2o), 0.95 (9H, s, SiC(CH3)3), 0.92 (9H, s, SiC(CH3)3), 0.76 (3H, d, J = 6.6 Hz, Me-|6), 0.14-0.07 (12H, m, 2 x Si(CH3)2).
Stage 16.1: (2,6-Dimethylphenyl) (2S, 3S, 4S, 5S, 6S, 7Z)-2-[(2Z, 4S, 5R, 6S)-5-(f- butyIdimethylsiIyloxy)-7-(p-methoxybenzyloxy)-2,4,6-trimethyl-hept-2-enyl]-3-hydroxy-5-(p- methoxybenzyloxy)-4,6-dimethyl-deca-7,9-dienoate
To a stirred solution of 1.14 g (2.00 mmol) of 2, 6-dimethylphenyl (4Z, 6S, 7R 8S)-7-(f- butyldimethylsilyloxy)-9-(p-methoxybenzyloxy)-4,6,8-trimethyl-4-nonenoate (prepared according to I. Paterson, G. Florence, et al, J. Am. Chem. Soc. 2001, 123, 9535-9544) in
THF (6 mL) at -100°C is added freshly prepared LiTMP (7.33 mL of a 0.3 M THF solution, 2.20 mmol). After 20 min at -100°C, a precooled (-100°C) solution of 288 mg (1.00 mmol) of aldehyde (Z)-(2S, 3S, 4S)-3-(p-Methoxybenzyloxy)-2,4-dimethyl-octa-5,7-dienal (prepared according to I. Paterson, G. Florence, et al, J. Am. Chem. Soc. 2001, 123, 9535-9544 or J. Nerenberg et al, J. Am. Chem. Soc. 1993, 115, 12621-12622) in THF (3 mL) is added via cannula. After 7 min at -100°C the reaction is quenched by the addition of MeOH (2 mL) and then NH4CI (10 mL). After warming to RT, the layers are separated and the aqueous layer is extracted with Et2θ (3 x 50 mL). The combined organics are dried (MgSO4) and concentrated in vacuo . Flash chromatography (5-10% EtOAc/Hexanes) gives recovered aryl ester and the desired aldol product as a viscous colourless oil; Rf 0.20 (15 % EtOAc/Hexane); IR (Thin film) 3494 (br, OH), 2960 (s), 2930 (s), 2856 (s), 1750 (m, C=0), 1613 (m), 1586 (w), 1520 (s), 1463 (m), 1250 (s); m/z (ES+) 879 (100, [M+Na]+).
Stage 16.2: (3Z, 5S, 6S, 7R 8S, 9R, 11Z, 13S, 14R 15S)-14-(f-Butyldimethylsilyloxy)-6,16- bis-(p-methoxybenzyloxy)-9-(hydroxymethyl)-5,7,11 ,13,15-pentamethyl-hexadeca-1 ,3,11- trien-8-ol
To a stirred solution of the aldol adduct of stage 16.1 (561 mg, 0.66 mmol) in THF (15 mL) at -78°C is added LiAIH4 (6.60 mL of a 1M/THF solution, 6.60 mmol). The reaction mixture is allowed to gradually warm to -15°C over 1 h. The reaction mixture is then quenched by the careful addition of potassium sodium tartrate (30 mL) and stirred vigorously at RT. After 30 min, the layers are separated and the aqueous layer is extracted with Et2θ (3 x 100 mL). The combined organics are dried (Na2Sθ4) and concentrated in vacuo . Flash chromatography (5-30% EtOAc/Hexanes) gives the desired diol as a colourless oil; Rf 0.13 (25%
EtOAc/Hexane); 1H NMR (500 MHz, CDCI3) δH 7.26-7.21 (4H, m, ArH), 6.90-6.82 (4H, m, ArH), 6.68 (1H, ddd, J = 16.7, 10.7, 10.6 Hz, H23), 6.07 (1H, dd, J = 11.0, 10.9 Hz, H22), 5.50 (1H, dd, J= 10.5, 10.4 Hz, H21), 5.24 (1H, d, J = 16.6 Hz, H24A), 5.15 (1H, d, J= 10.3 Hz, H 4B). 5.04 (1H, d, J = 10.0 Hz, H13), 4.70 (1H, d, J = 10.2 Hz, CHAHBAΓ), 4.43-4.35 (3H, m, CIHAHBAΓ + CH^Ar), 3.81-3.77 (1H, m0bs> OH), 3.79 (6H, s, 2 x OCH3), 3.69-3.63 (2H, m, H17 + H25A). 3.54-3.47 (2H, m, H9A + H25B). 3.39 (1H, dd, J = 6.3, 4.4 Hz, H19), 3.36 (1H, dd, J = 5.6, 4.5, Hz, Hn), 3.32 (1H, dd, J = 7.4, 3.1 Hz, OH), 3.20 (1H, dd, J = 8.7, 8.3 Hz, H9B), 3.07 (1H, ddq, J = 9.8, 6.9, 6.8 Hz, H2o), 2.54-2.45 (1H, m, H12), 2.01-1.91 (2H, m, H10 + H15A). 1.91-1.83 (2H, m, H16 + H-|8), 1.65-1.60 (1H, mobs, H15B), 1-62 (3H, s, Me-14), 1.03 (3H, d, J = 6.9 Hz, Me2o). 1-01 (3H, d, J = 7.0 Hz, Me<|8), 0.94 (3H, d, J = 7.0 Hz, Meio), 0.91-0.87 (12H, m, Me-|2 + SiC(CH3)3), 0.02 (6H, s, Si(CH3)2).
Stage 16.3: (3Z, 5S, 6S, 7R, 8S, 9R 11Z, 13S, 14R 15S)-14-(f-Butyldimethylsilyloxy)-6,16- bis-(p-methoxybenzyloxy)-9-[(2,4,6-trimethylphenyl)sulfoxymethyl]-5,7,11,13,15- pentamethyl-hexadeca-1 ,3,11 -trien-8-ol To a stirred solution of the diol of stage 16.2 (715 mg, 0.97 mmol) in CH2CI2 (15 mL) at RT is added Et3N (683 μL, 4.85 mmol), and 2,4,6-trimethylphenyl sulfonylchloride (318 mg, 1.45 mmol). After 20 h the mixture is partitioned between NaHC03 (20 mL) and CH2CI2 (3 x 50 mL). The combined organic extracts are dried (Na2S04) and concentrated in vacuo. Flash chromatography (10-20% EtOAc/Hexanes) gives the title compound as viscous colourless oil; Rf 0.37 (25% EtOAc/Hexane); m/z (ES+) 943 (100, [M+Na]+), 743 (28), 339 (20).
Stage 16.4: (3Z, 5S, 6S, 7S, 8R, 9S, 11Z, 13S, 14R 15S)-14-(f-Butyldimethylsilyloxy)-6,16- bis-(p-methoxybenzyloxy)-5,7,9,11,13,15-hexamethyl-hexadeca-1,3,11-trien-8-ol To a stirred solution of the sulfonate of stage 16.3 (536 mg, 0.583 mmol) in THF (20 mL) is added UAIH4 (5.83 mL of a 1M/THF solution, 5.83 mmol) at -78°C and allowed to gradually warm to -10°C over 1.5 h. The reaction is then quenched by the addition of MeOH (4 mL), then partitioned between potassium sodium tartrate (30 mL) and Et2θ (3 x 100 mL). The combined organic extracts are dried (MgSθ4) and concentrated in vacuo. Flash chromatography (10% EtOAc/Hexanes) gives the desired product as colourless oil; Rf 0.45
(25% EtOAc/Hexane); [α]2° +27.3 (c 1.3, CHCI3); 13C NMR (100 MHz, CDCI3) δC 159.2,
159.1, 135.1, 134.3, 132.3, 131.6, 130.9, 130.6, 129.4, 129.3, 129.1, 117.8, 113.8, 113.7, 86.8, 78.7, 78.3, 74.2, 72.6, 72.6, 55.3 (2C), 38.5, 37.3, 35.7, 35.5, 35.3, 34.2, 26.2, 23.2,
18.4, 18.3, 17.1, 15.0, 14.9, 7.8, -3.9 (2C); m/z (ES+) 745 (100, [M+Na]+).
Stage 16.5: (3Z, 5S, 6S, 7S, 8R 9S, 11Z, 13S, 14R 15S)-8,14-Bis(f-butyldimethylsilyloxy)-
6,16-bis-(p-methoxybenzyloxy)-5,7,9,11,13,15-hexamethyl-hexadeca-1 ,3,11-triene
To a stirred solution of the alcohol of stage 16.4 (400 mg, 0.554 mmol) in CH2CI2 (10 mL) at
-78°C is added Et3N (780 μL, 5.54 mmol), followed by addition of TBSOTf (635 μL, 2.77 mmol). The reaction mixture is allowed to warm to RT and stirred for 4 hr. The reaction mixture is then partitioned between NaHCC-3 (20 mL) and CH2CI2 (3 x 50 mL). The combined organic extracts are dried (MgSθ4) and concentrated in vacuo. Flash chromatography (5% EtOAc/Hexanes) provides the desired product as colourless oil; Rf 0.54 (20%
EtOAc/Hexane); [ ]2° +27.1 (c 0.44, CHCI3); 13C NMR (100 MHz, CDCI3) δC 159.0, 159.0,
134.5, 132.2, 131.8, 131.2, 131.2, 131.0, 129.1, 129.0 (2C), 117.6, 113.7 (2C), 84.6, 78.4, 77.1 , 75.0, 72.7, 72.5, 55.3 (2C), 40.5, 38.8, 36.0, 35.5, 35.4, 30.9, 26.3, 26.1, 23.0, 18.7,
18.6, 18.4, 17.2, 14.7, 14.4, 10.6, -3.2, -3.3, -3.9 (2C); HRMS (ES+) calcd for
C5θH84θ6Si2Na [M+Na]+ 859.5704, found 859.5709.
Stage 16.6: (2S, 3R 4S, 5Z, 8S, 9R, 10S, 11S, 12S, 13Z)-3,9-Bis-(f-butyldimethylsilyIoxy)- 2,4,6,8,10, 12-hexamethyl-hexadeca-5, 13, 15-triene-1 , 11 -diol
To a stirred solution of bis-PMB ether of stage 16.5 (428 mg, 0.512 mmol) in CH2CI2 (12 mL) and pH 7 buffer (1.2 mL) at 0°C is added DDQ (291 mg, 1.28 mmol). After 2.5 h, the reaction mixture is partitioned between NaHCθ3 (50 mL) and CH2CI2 (3 x 100 mL). The combined organic extracts are washed NaHC03 (50 mL), dried (MgSθ4) and concentrated in vacuo. Flash chromatography (30% EtOAc/Hexanes) gives the desired diol as a colourless oil; Rf 0.21 (25% EtOAc/Hexane); m/z (ES+) 619 (100, [M+Na]+).
Example 17: Methyl (2R 3S. 4R)-3-(fert-butyldimethylsilyloxy)-2,4-dimethyl-5-oxo- pentanoate
Oxalylchloride (distilled, 29 ml, 0.33 mmol, 1.5 eq) is dissolved in dichloromethane (1 ml) and cooled to -78°C. DMSO (47 ml, 0.66 mmol, 3 eq) is added and the reaction mixture is stirred for 30 min. The semi crude alcohol from stage 17.4 (max 0.219 mmol) is added in dichloromethane (2 ml) via cannula and the reaction mixture is stirred for 45 min at -78°C. Triethylamine (214 ml, 1.53 mmol, 7 eq) is added and the mixture is stirred for 20 min at -78°C before being allowed to warm up slowly to RT. Hexane / Et2θ (2 : 1) is added to induce precipitation and the mixture is filtered over celite. Evaporation of solvents and purification by flash chromatography (silica gel, 10% EtOAc / hexane) yields the desired aldehyde as a colourless oil; Rf 0.58 (33% EtOAc / hexane); IR (Thin Film) 2954 (s), 2885 (m), 2858 (m),
1732 (s, CO), 1462 (m), 1435 (w), 1388 (w), 1362 (w), 1323 (w), 1255 (m); m/z (ES+) 311 (100, [M+Na]+). Stage 17.1: (2R, 3S, 4S)-2,4-dimethyl-3-hydroxy-5-(4-methoxybenzyloxy)pentanoic acid Crude aldehyde of Example 15 (max 1.866 mmol) is dissolved in t-BuOH (5 ml) and 2- methyl-2-butene (1 ml). A solution of sodium chlorite (422 mg, 3.73 mmol, 2 eq) and sodium dihydrogenphosphate dihydrate (1.75 g, 11.2 mmol, 6 eq) in water (5 ml) is added slowly at 0°C. After stirring for 1 h at RT the mixture is diluted with water (20 mL), extracted with Et2θ (7 x 10 mL), washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford the title compound, which can be used without further purification; Rf 0.11 (50% EtOAc / hexane); IR: 3450 (m, br), 2936 (s), 1708 (s, CO), 1612 (s), 1586 (m), 1514 (s), 1460 (s), 1302 (m), 1248 (s); m/z: (El) 282 (100, M+), 264 (33), 235 (43), 208 (52).
Stage 17.2: Methyl (2R, 3S, 4S)-2,4-dimethyl-3-hydroxy-5-(4-methoxybenzyloxy)pentanoate The acid of stage 17.1 (max 1.866 mmol) is dissolved in DMF (5 ml). Potassium carbonate (313 mg, 2.26 mmol, 1.2 eq) is added, followed by iodomethane (176 mL, 2.83 mmol, 1.5 eq). After stirring for 2 h, the reaction mixture is diluted with water (20 mL), extracted with EtOAc (5 x 10 mL). The combined organic extracts are dried (Na2S04) and concentrated in vacuo. The crude mixture is purified by flash chromatography (silica gel, 10% EtOAc in hexane) yielding the desired ester as a white solid with a mp of 56 °C.
Stage 17.3: Methyl (2R 3S, 4S)-3-(fert-butyldimethylsilyloxy)-2,4-dimethyl-5-(4-methoxy benzyl oxy)pentanoate
To a stirred solution of the ester of stage 17.2 (810 mg, 2.73 mmol) in dry dichloromethane (30 ml) at -78°C are added 2,6-lutidine (511 ml, 4.39 mmol, 1.6 eq) and TBSOTf (757 ml, 3.29 mmol, 1.2 eq). The solution is stirred in the cooling bath for 3 h, being allowed to warm up slowly, reaching a temperature of -15°C, before warming up to RT. Addition of aqu. NaHC03 (20 mL) is followed by extraction with dichloromethane (5 x 10 mL). Drying (MgSθ4), evaporation of solvents and purification by flash chromatography (silica gel, 7% EtOAc in hexane) gives the title compound as a colourless oil; Rf 0.35 (14% EtOAc / hexane); 1 H NMR (250 MHz, CDCI3) dπ 7.26 (2H, d, J = 8.7 Hz, PMB), 6.88 (2H, d, J = 8.7 Hz, PMB), 4.44 (1 H, d, J = 11.9 Hz, PMB), 4.38 (1 H, d, J = 11.8 Hz, PMB), 4.06 (1H, dd, J = 5.9, 4.6 Hz, H3), 3.81 (3H, s, OMe-PMB), 3.64 (3H, s, OMe- ester), 3.50 (1H, dd, J = 9.1, 4.8 Hz, H5A). 3.26 (1H, dd, J = 9.1, 7.2 Hz, H5B), 2.66 (1H, dq, J = 7.0, 4.6 Hz, H2), 1.92 (1 H, m, H4), 1.13 (3H, d, J = 7.0 Hz, Mθ2), 0.98 (3H, d, J = 7.0 Hz, Me4), 0.89 (9H, s, SiC(CH3)3), 0.03 (3H, s, SiCH3), -0.01 (3H, s, SiCH3).
Stage 17.4: Methyl (2R, 3S, 4S)-3-(ferf-butyldimethylsilyloxy)-2,4-dimethyl-5-hydroxy pentanoate
To a stirred solution of the compound of stage 17.3 (60 mg, 0.198 mmol) in dichloromethane (2 mL) and pH7 buffer (0.2 ml) at 0°C is added recrystallised DDQ (63 mg, 0.277 mmol). The solution is stirred at 0°C for 30 min, then at RT for 45 min. Hexane : Et2θ (2:1) is added to induce precipitation and the reaction mixture is filtered over celite. After evaporation of solvents the crude mixture is quickly purified by flash chromatography over a short plug of silica (33% Et2θ / hexane) to give as a colourless oil; Rf 0.17 (20% EtOAc / hexane); IR (Thin Film) 3452 (br m, OH), 2954 (s), 2885 (s), 2857 (s), 1732 (s, CO), 1472 (s), 1462 (s), 1436 (m), 1387 (m), 1361 (m), 1312 (w), 1254 (s).
Example 18: (3Z. 5S. 6S. 7S. 8Z. 11S. 12R 13S. 14S. 15S. 16Z)-6. 12 -Bis-(t- butyldimethylsilyloxy)-14-hydroxy-5. 7, 9 .11 .13 ,15 -hexamethylnonadeca-3 .8 ,16 ,18 - tetraen-2-one
18-crown-6 (2.44 g, 9.26 mmol, 12 eq) and K2CO3 (640 mg, 4.631 mmol, 6 eq, ground and dry heated) are stirred in toluene (4 ml) and HMPA (0.4 ml) at RT for 3 h before cooling to - 15°C. The Still-Gennari reagent of stage 18.2 (932 mg, 3.087 mmol, 4 eq) and the aldehyde of Example 16 are dissolved in toluene (4 mL) and HMPA (0.4 mL) and added to the reaction mixture via cannula. The mixture is stirred for 5 h with slowly warming to 4°C before being left over night in the fridge. The reaction is quenched by addition of sat. aqu. NH4CI solution, extracted with CH2CI2 (3 x 15 mL). The combined organic extracts are washed with water, dried ( a2S04), and concentrated in vacuo. 1H NMR of the crude mixture shows that it contains the cis product and the trans product in a 12 : 1 ratio. Purification by flash chromatography (silica gel, 7% EtOAc / hexane) yields the cis methylketone as a white foam; Rf 0.54 (33% EtOAc / hexane); 1H NMR (400 MHz, CDCI3) δH 6.64 (1 H, ddd, J = 16.8, 10.3, 10.3 Hz, H23). 6.22 (1H, dd, J = 11.6, 9.6 Hz, Hg), 6.15 (1H, dd, J = 11.0, 11.0 Hz, H22), 6.07 (1H, d, J = 11.6 Hz, H8), 5.35 (1H, dd, J = 10.5, 10.5 Hz, H21), 5.25 (1H, dd, J = 16.8, 1.8 Hz, H24trans). 5.16 (1H, d br, J = 10.1 Hz, H24cis). 4.91 (1H, d br, J = 10.3 Hz, H13), 3.61 (1H, dd, J = 5.56, 3.3 Hz, H17), 3.63-3.53 (1H, m, H-|0), 3.38 (1H, dd, J = 7.4, 2.9 Hz, H-n), 3.35 (1H, m, J = 7.6 Hz, H19), 2.82 (1H, ddq, J = 9.9, 7.0, 7.0 Hz, H20), 2.35 (1H, ddq, J = 10.2, 7.0, 7.0 Hz, H12), 2.17 (3H, s, H6), 2.15 (1H, dd, J = 12.5, 12.5 Hz, H15A), 1.92-1.76 (2H, m, Hι6 + H-|8), 1.67 (1H, d br, J = 12.6 Hz, H<|5B)> 1-57 (3H, s, Me-| ), 1.62- 1.54 (1H, m, OH), 1.01 (3H, d, J = 7.0 Hz, Meio), 0.98 (3H, d, J = 6.9 Hz, Me2o)> 0.96 (3H, d, J = 7.0 Hz, Meιs), 0.93 (18H, m, SiC(CH3)3), 0.9 (3H, d, J = 6.6 Hz, Me-|2), 0.72 (3H, d, J= 6.8 Hz, Mei6), 0.12-0.08 (12H, m, SiCH3); m/z (ES+) 657 (71, [M+Na]+).
Stage 18.1: Methylphosphonic acid bis(2,2,2-trifluoroethyl) ester A solution of trifluoroethanol (5.48 mL, 75.2 mmol, 2 eq) and triethylamine (11.6 mL, 83.1 mmol, 2.21 eq) in THF (125 mL) is cooled to 10°C. A solution of methanephosphonic dichloride (5.00 g, 37.6 mmol, 1 eq) in THF (20 mL) is added via a dropping funnel. A precipitate forms, the mixture is stirred at RT for 2 h, the precipitate is filtered off, washed with THF (60 mL) and the filtrate is concentrated in vacuo. Purification by Kugelrohr distillation (83°C, 15 mmHg) gives as a colourless oil; H NMR (400 MHz, CDCI3) 6H 4.45 - 4.25 (4H, m, OCH2), 1.63 (3H, d, JPH = 18.2 Hz, CH3).
Stage 18.2: (2-Oxo-propyl)phosphonic acid bis(2,2,2-trifluoroethyl) ester A solution of the product of stage 18.1 (8.54 g, 32.8 mmol) and acetyl chloride (2.8 mL, 39.4 mmol, 1.2 eq) in THF (10 mL) is added slowly via cannula to LiHMDS (69 mL of a 1M solution in THF, 69 mmol, 2.1 eq) at -98°C. After addition the mixture is stirred for 1 h before being quenched 3N HCI (20 mL) and allowed to warm up to RT. The aqu. layer is extracted with CH2CI2 (3 x 30 mL), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The product (4.95 g, 50%) is obtained as a colourless oil by Kugelrohr distillation at 110°C / 3 mmHg;lH NMR (400 MHz, CDCI3) Dn.4.49 - 4.35 (4H, m, O-CH2), 3.27 (2H, d, JPH = 21.8 Hz, CH2-P), 2.29 (3H, s, CH3).
Example 19: (3Z. 5S. 6S. 7S. 8Z. 11S, 12R 13S, 14S, 15S. 16Z)- 6, 12 -Bis-(f- butyldimethylsilyloxy) -14-carbamoyloxy-5. 7 .9 .11 .13 .15 -hexamethylnonadeca-3, 8. 16. 18 -tetraen-2-one
To a stirred solution of the ketone of Example 18 (500 mg, 0.788 mmol) in dry CH2CI2 (14 ml) at RT is added trichloroacetyl isocyanate (141 μl, 1.183 mmol, 1.5 eq). After stirring for 1 h, the reaction mixture is put on a plug of neutral alumina with CH2CI2 and kept there for 2 h. The substrate is washed from the alumina with EtOAc. After evaporation of solvents and purification by flash chromatography (silica gel, 10% EtOAc / hexane), the desired carbamate is obtained as a white foam; Rf: 0.17 (20% EtOAc / hexane); 1H NMR (400 MHz, CDCI3) δH 6.60 (1H, ddd, J = 16.8, 10.4, 10.4 Hz, H23), 6.19 (1H, dd, J = 11.6, 9.6 Hz, Hg),
6.05 (1 H, d, J = 12.1 Hz, H8), 6.03 (1 H, dd, J = 11.0, 11.0 Hz, H22), 5.38 (1 H, dd, J = 10.6, 10.6 Hz, H21), 5.22 (1H, dd, J = 16.8, 1.7 Hz, H24trans). 5.13 (1H, d br, J = 10.1 Hz, H24cis). 4.88 (1H, d br, J = 10.3 Hz, H13), 4.73 (1H, dd, J = 6.1, 6.1 Hz, Hig), 4.56 (2H, s br, NH2), 3.56 (1H, ddq, J = 9.5, 7.1, 2.5 Hz, H10), 3.43 (1H, dd, J = 4.4, 4.4 Hz, H17), 3.37 (1H, dd, J = 7.4, 2.3 Hz, H11), 2.99 (1H, ddq, J = 10.1, 6.8, 6.8 Hz, H2υ), 2.32 (1H, ddq, J = 10.3, 6.6,
6.6 Hz, H12), 2.16 (3H, s, H6), 2.06 (1H, dd, J = 12.3, 12.3 Hz, Hi5A), 1.94 - 1.77 (2H, m, H16 + His), 1-6 (1H, d br, J = 12.6 Hz, Hι5B), 1.56 (3H, s, Meι4), 1.02 - 0.97 (6H, 2xd, J = 7.0 + 6.7 Hz, Me-io + Me o), 0.96 - 0.89 (21 H, m, Meι8 + SiC(CH3)3), 0.88 (3H, d, J = 6.6 Hz, Mei2), 0.69 (3H, d, J = 6.7 Hz, Me16), 0.12 - 0.06 (12H, m, SiCH3); m/z (ES+) 700 (100, [M+Na]+).
Example 20: Methyl (2R 3S. 4S. 5S. 8Z. 10S, 11S, 12S, 13Z. 16S, 17R 18S, 19S. 20S. 21Z.)-3,7.11-tris(t-butyldimethylsilyloxy)-19-carbamoyloxy-5-hvdroxy-2. 4. 10. 12. 14, 16. 18. 20-octamethyl-7-oxotetracosa-8. 13. 21. 23-tetraenoate
To a solution of the ketone of Example 19 (45 mg, 0.066 mmol) in dry Et2θ (500 μl) is added cHex2BCI (44 μl, 0.198 mmol, 3 eq) and immediately afterwards triethylamine (31 μl, 0.217 mmol, 3.2 eq) at 0°C. After 30 min enolisation at 0°C, the reaction mixture is cooled at -78°C. 57 mg (0.198 mmol, 3 eq) of the freshly prepared product from Example 17 (dissolved in 1.5 ml of Et2θ and dried over CaH2) is added via cannula. After stirring at -78°C for 6 h, the reaction mixture is stored for 17 h in the freezer at -78°C. It is then quenched by the addition of pH7 buffer (3 mL). After extraction with ethyl acetate (4 x 5 mL), washing with NaHC03 and brine, drying (Na2S04) and evaporation of most of the solvent, the reaction mixture is purified by preparative TLC (eluent syste : 33% EtOAc / hexane) to give the desired product as a white foam; Rf: 0.5 (33% EtOAc / hexane); 13C NMR (100 MHz, CDCI3) δc 200.8, 176.2, 157.0, 152.1, 133.6, 132.7, 132.1, 130.3, 129.7, 125.4, 117.9, 80.5, 78.6, 77.0, 73.7,
68.6, 51.7, 47.5, 43.9, 42.5, 38.1 (2C), 37.7, 36.2, 34.8, 34.4, 26.2 (2C), 25.9, 18.5, 18.4,
22.7, 18.2, 17.6, 17.5, 13.6, 12.3, 11.6, 10.1, -3.4, -3.5 (2C), -3.8, -4.4, -4.5. Example 21: 3. 11. 17-Tris-(t-butyldimethylsilyl)-7-oxo-discodermolide
The aldol from Example 20 (13 mg, 0.0134 mmol) is dissolved in THF (0.5 mL). Water (0.5 mL) is added, followed by AcOH (0.5 mL). The reaction mixture is stirred at RT for 3 days, before being partitioned between aqu. NaHC03 (10 mL) and EtOAc (5 mL). The aqu. layer is re-extracted with EtOAc (5 x 5 mL). The combined organic extracts are dried (Na2S04), and concentrated under vacuum. The crude product is purified by flash chromatography (Silica gel, 20% EtOAc / Hexane) to give the desired product as a white solid.
Rf 0.21 (20% EtOAc / Hexane); [af£ +77.8 (c 1.3, CHCI3); IR (Thin film) 3372 (br m,
CONH2), 2958 (s), 2931 (s), 2857 (s), 1732 (s, C=0), 1606 (w), 1472 (m), 1385 (m); 1H NMR (500 MHz, CDCI3) δH 6.60 (1H, ddd, J = 16.6, 10.7, 10.6 Hz, H23), 6.25 (1H, dd, J = 11.3, 9.8 Hz, Hg), 6.10 (1H, d, J = 11.5 Hz, H8), 6.03 (1H, dd, J = 11.1, 11.0 Hz, H22), 5.39 (1H, dd, J = 10.6, 10.5 Hz, H2-|), 5.22 (1H, d, J = 16.2 Hz, H24A), 5.14 (1H, d, J = 10.2 Hz, H24B)> 4.86 (1H, d, J = 10.2 Hz, H13), 4.77 (1H, ddd, J = 9.7, 5.0, 5.0 Hz, H5), 4.74 (1H, dd, J = 6.2, 6.0 Hz, H19), 4.61 (2H, br s, CONH2), 3.66 (1 H, dd, J = 2.8, 2.8 Hz, H3), 3.63 - 3.54 (1H, m, H10), 3.45 - 3.35 (2H, m, Hn + H-|7), 2.99 (1H, ddq, J = 10.0, 6.6, 6.0 Hz, H2o), 2.86 (1H, dd, J = 16.1, 5.4 Hz, H6A), 2.70 (1H, dd, J = 16.1, 5.0 Hz, H6B), 2.63 (1H, qd, J = 7.4, 3.6 Hz, H2), 2.38-2.27 (1H, m, H12), 2.20 - 2.08 (1H, m, H4), 2.08 - 2.00 (1H, m, H15A), 1.90 - 1.80 (2H, m, H-I6 + His), 1-65 - 1.57 (1H, m, Hι5β). 1-57 (3H, s, Me ), 1.30 - 1.20 (3H, m, Me2), 1.08 - 0.95 (9H, 3 x d, J = 6.0, 6.6, 7.0 Hz, Mβ20, Mβ4, Meio), 0.95 - 0.80 (33H, , Meis + Mei2 + SiC(CH3)3), 0.69 (3H, d, J = 6.8 Hz, Me16), 0.15 - 0.05 (18H, m, SiCH3); m/z (ES+) 956 (100, [M+Na]+).
Example 22: 3. 11. 17-Tris-(t-butyldimethylsilyl)-discodermolide
The keto-lactone from from Example 21 (11 mg, 0.012 mmol) is dissolved in toluene (2 mL) and the solution is cooled down to -78°C. K-Selectride (1M in THF, 0.024 mmol, 24 μL, 2 eq) is added and the reaction mixture is stirred at -78°C for 3 h, before being quenched with one drop of AcOH and allowed to warm up to RT. pH7 buffer (2 mL) is added, followed by 1 drop of H2O2 (30% solution), and the reaction mixture is stirred at RT for 45 min. After dilution with pH7 buffer (5 mL), the aqu. layer is extracted with CH2CI2 (4 x 5 mL), and EtOAc (2 x 5 mL). The combined organic extracts are dried (Na2SO4), and concentrated under vacuum. Flash chromatography on silica gel (15% EtOAc / Hexane) yields the title compound as a white solid. Rf: (33% EtOAc / hexane); IR (Thin film) 3508 (br, OH), 2958 (s), 2930 (s), 2856
(s), 1726 (s, C=0), 1597 (w), 1462 (m), 1386 (m); 1H NMR (400 MHz, CDCI3) δH 6.60 (1H, ddd, J = 16.8, 10.7, 10.6 Hz, H23), 6.03 (1H, dd, J = 11.0, 11.0 Hz, H22). 5.51 (1H, dd, J = 10.3, 10.3 Hz, Hg), 5.40 - 5.30 (2H, m, H21 + H8), 5.22 (1H, d, J = 16.8 Hz, H24A), 5.14 (1H, d, J = 10.0 Hz, H24B). 5.01 (1H, d, J = 10.0 Hz, H13), 4.79 - 4.65 (1H, m, H7), 4.72 (1H, dd, J = 6.1, 6.0 Hz, Hig), 4.60 (1H, ddd, J = 10.2, 10.1, 2.2 Hz, H5), 4.51 (2H, br s, CONH2), 3.67 (1H, dd, J = 2.8, 2.8 Hz, H3), 3.41 (1H, dd, J = 4.5, 4.5 Hz, H17), 3.27 (1H, dd, J = 5.9, 4.6 Hz, H11), 3.02 - 2.98 (1H, m, H20), 2.78 - 2.69 (1H, m, H10), 2.65 (1H, ddd, J = 15.2, 7.6, 3.2 Hz, H2), 2.47 - 2.38 (1H, m, H12), 2.09 (1H, dd, J = 12.8, 12.8 Hz, Hι5A), 1.97 - 1.74 (5H, m, H4 + H6A + H16 + His + OH), 1.70 - 1.68 (2H, m, H6β + Hι5B), 1-59 (3H, s, Me ), 1.25 (3H, d, J = 7.5 Hz, Mβ2), 1.05 - 0.85 (42H, m, J = 6, Mβ4, Me20, Meιn, Meiβ, Mei2, SiC(CH3)3), 0.71 (3H, d, J = 6.8 Hz, Meι6), 0.11 - 0.02 (18H, m, SiCH3).
Example 23: (+)-Discodermolide
To a stirred solution of the prodcut from Example 22 (6.2 mg, 0.0066 mmol) in MeOH (0.6 mL) at 0°C is added dropwise 3N HCI (0.2 mL). The reaction mixture is stirred at RT for 4 days, it is then partitioned between aqu. NaHCO3 (5 mL) and CH2CI2 (5 mL). The aqu. layer is re-extracted with CH2CI2 (3 x 5 mL) and EtOAc (4 x 5 mL). The combined organic extracts are dried (Na2Sθ4), concentrated under vacuum, and the residue is purified by flash chromatography (silica gel, 5% MeOH in DCM), to give (+)-Discodermolide as a white solid; Rf: 0.20 (10% MeOH / DCM); [α]2° +13.2 (c 1.1, CHCI3); 1H NMR (400 MHz, CDCI3) δπ 6.62 (1H, ddd, J = 16.8, 10.6, 10.6 Hz, H23)> 6.03 (1H, dd, J = 11.0, 11.0 Hz, H22), 5.53 (1H, dd, J = 11.1, 7.9 Hz, H8), 5.43 (1H, dd, J = 10.7, 10.3 Hz, Hg), 5.36 (1H, dd, J = 10.5, 10.2 Hz, H21), 5.22 (1H, d, J = 16.8Hz, H24A), 5.17 (1H, d, J = 9.7 Hz, H13), 5.13 (1H, d, J = 10.1 Hz, H24B). 4.75 (1H, ddd, J = 7.5, 7.5, 2.6 Hz, H7), 4.71 (1H, dd, J = 7.2, 4.2 Hz, H19), 4.63 (1H, ddd, J = 10.0, 9.8, 2.1 Hz, H5), 4.61 (2H, s br, NH2), 3.75 (1H, dd, J = 4.0, 4.0 Hz, H3), 3.29 (1H, dd, J = 4.9, 4.5 Hz, H17), 3.20 (1H, dd, J = 6.6, 4.9 Hz, Hn), 3.00 (1H, ddq, J = 9.9, 6.9, 6.9 Hz, H2o), 2.80 (1H, ddq, J = 9.7, 6.8, 6.8 Hz, H10), 2.68 (1H, dq, J = 7.3, 4.5 Hz, H ), 2.65 - 2.53 (1H, m, Hι2), 2.10 - 1.80 (10H, m, H + H6A + Hι5A + H15B + Hie + His + 4 x OH), 1.74 - 1.67 (1H, m, H6B), 1 -65 (3H, s, Me1 ), 1.32 (3H, d, J = 7.3 Hz, Me2), 1.08 (3H, d, J = 6.9 Hz, Mβ4), 1.02 (3H, d, J= 6.8 Hz, Meio), 1.00 (3H, d, J = 5.9 Hz, Me2o), 0.99 (3H, d, J = 6.3 Hz, Meι8), 0.95 (3H, d, J = 6.8 Hz, Mei2), 0.83 (3H, d, J = 5.7 Hz,
Meιβ); HRMS (ES+) calcd for C33H55θβNNa [M+Na]+ 616.3825, found 616.3839.
Stage 24: Methyl (2R.3S,4R)-3-triethylsilyloxy-2,4-dimethyl-5-oxo-pentanoate Methyl (2R3S,4R)-3-triethylsilyloxy-2,4-dimethyl-5-oxo-pentanoate may be prepared according to example 17 wherein TESOTf is used instead of TBSOTf in stage 17.3.
Ester of stage 24.1.6 (250 mg, 0.608 mmol) is dissolved in DCM (10 mL). pH 7 buffer (1 mL) is added, and the solution is cooled to 0°C. DDQ (166 mg, 0.731 mmol, 1.2 eq.) is added slowly, and the reaction mixture is stirred for 30 min at 0°C, and for 45 min at RT. pH 7 buffer (50 mL) is added to the mixture, and it is extracted with AcOEt (3 x 25 mL). The combined organic extracts are dried over Na2Sθ4 and concentrated under vacuum. This affords a mixture of the free primary alcohol and p-anisaldehyde, which is used without any further purification. It is redissolved in DCM (5 mL), TEMPO (19 mg, 0.122 mmol, 0.2 eq.) is added, followed by bis-acetoxyiodobenzene (588 mg, 1.824 mmol, 3 eq.), and the reaction mixture is stirred at RT for 2 h. A saturated aqueous solution of aS2U3 (100 mL) is added, and the mixture is vigorously stirred for 15 min. The aqueous layer is extracted with DCM (4 x 50 mL). The combined organic extracts are dried (Na2Sθ4), and concentrated under reduced pressure. Purification by flash chromatography on silica gel affords aldehyde as a slightly coloured oil.
Rf 0.57 (33% AcOEt / Hex); 1H NMR (400MHz, CDCI3) δH : 9.71 (1H, d, J = 2.1 Hz, CHO);
4.30 (1 H, dd, J = 5.5, 5.5 Hz, H3); 3.66 (3H, s, OMe); 2.64 (1 H, dq, J = 7.0, 5.7 Hz, H2); 2.52
(1H, ddq, J = 7.2, 5.3, 2.1 Hz, H4); 1.19 (3H, d, J = 7.1 Hz, Me2); 1.08 (3H, d, J = 7.1 Hz,
Me4); 0.93 (9H, t, J = 8.0 Hz, Si(CH2CH3)3); 0.63 (6H, q, J = 8.0 Hz, Si(CH2CH3)3); 1 C NMR (100 MHz, CDCI3) δc: 203.5, 174.8, 74.5, 51.8, 51.2, 43.4, 12.0, 10.7, 6.8, 5.0.
Stage 24.1: 2R. 3S. 4S-3-(triethylsilanyloxy)-5-(4-methoxybenzyloxy)-2.4-dimethylpentanoic acid methoxy-methyl amide.
A solution of 3-Hydroxy-5-(4-methoxy-benzyloxy)-2,4-dimethyl-pentanoic acid methoxy- methyl-amide prepared according to Amos B. Smith; J. Am. Chem. Soc; 2000; 122(36) pp 8654 - 8664 (25 g, 76.8 mmol) in toluene (84.0 g) is cooled to an internal temperature of between 0 - 5°C, 2,6-lutidine is added (10.7 g, 99.85m mol) followed by drop wise addition of triethylsilyl triflate (24.4 g, 92.3 mmol) within 30 minutes maintaining the temperature between 0 - 5°C. The reaction mixture is stirred for 30 - 60 minutes at 0 - 5°C and treated with sodium hydrogen sulphate (120 g of a 10% solution). The phases are separated and the aqueous phase is re-extracted with toluene (63 g). The combined organic phases are washed twice with water (2 x 120 g) and the solvent removed in vacuum at 40°C to give 37 g, 110% of the crude silyl ether as an oil. This crude material is chromatographed in two portions of 18 g over silica gel (150 g) eluting initially with heptane/ethyl acetate 15/1 followed by ethyl acetate to gives the purified product as an oil. 1 H-NMR (300 MHz, CDCI3), δ 7.25 (m, 2H), 6.85 (m, 2H), 4.40 (s, 2H), 3.93 (dd, J = 8.17 & 2.53 Hz, 1H), 3.79 (s, 3H), 3.58 (m, 4H), 3.18 (dd, J = 9.8 & 8.2 Hz, 1H), 3.10 (s, 3H), 1.84 (Brm, 1H), 1.15 (d, J = 7 Hz, 3H), 0.94 (m, 15H), 0.60 (t, 9H).
Stage 24.2: (2R, 3S, 4S)- 3-triethylsilyloxy-Λ/-methoxy-5-(4-methoxybenzyloxy)-Λ/.2.4- trimethyl-pentanamide
Compound of stage 24.1 (2.02 g, 6.21 mmol) is dissolved in DCM (50 mL) and cooled to -78°C. Triethysilyltrifluoromethane sulfonate (1.69 mL, 7.45 mmol, 1.2 eq.) is added dropwise, and the reaction mixture is stirred at -78°C for 2 h, then at -50°C for 2 h, before being allowed to warm up to RT. The reaction system is diluted with aq. NaHCO3(100 mL). The aqueous layer is extracted with AcOEt (4 x 50 mL). The combined organic extracts are dried over Na2S04, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hept : AcOEt, 8:1 to 4:1) affords a colourless oil.
Rf 0.54 (33% AcOEt / Hex); [α]2^ -10.4 (c 1, CHCI3); IR (thin film) : 2958 (s), 2911 (s), 2877
(s) (CH), 1660 (s, C=0), 1613 (m), 1514 (s) (Bz), 1248 (s, Bz-O), 1173 (m, N-CH3), 1083
(s), 1040 (s), 998 (s) (Si-0 + C-O + N-O); "Η NMR (400MHz, CDCI3) δH : 7.20 (2H, d, J =
8.7 Hz, PMB); 6.81 (2H, d, J = 8.7 Hz); 4.37 (2H, m, PMB); 3.91 (1H, dd, J = 8.1, 3.1 Hz, H3); 3.74 (3H, s, PMB-OMe); 3.52 (1H, dd, J = 9.3, 5.1 Hz, H5A); 3.48 (3H, br s, N-Me); 3.14
(1H, dd, J = 9.1, 7.7 Hz, H5β); 3.20 - 3.00 (1H, m H2); 3.07 (3H, s, N-OMe); 1.86 (1H, , H4); 1.24 (3H, d, J = 7.0 Hz, Me2); 0.97 (3H, d, J = 6.9 Hz, Me4); 0.93 (9H, t, J = 8.0 Hz, Si(CH2CH3)3); 0.57 (6H, q, J = 8.0 Hz, Si(CH2CH3)3); 13C NMR (100 MHz, CDCI3) δc : 176.5, 158.8, 130.6, 129.0, 113.4, 76.4, 72.4, 71.5, 60.9, 54.9, 39.0, 38.3, 31.8, 15.3, 14.4, 6.9, 5.2; m/z (ES+): 462.3 (100, [M+Na]+); 440.3 (7, [M+H]+); HRMS (ES+) calcd for C23H41N05SiNa [M+Na]+ 462.2652, found 462.2664.
Stage 24.3: (2R 3S. 4S)- 3-triethylsilyloxy-5-(4-methoxybenzyloxyV2,4-dimethyl-pentanal Weinreb amide of stage 24.2 (1.68 g, 3.82 mmol) is dissolved in toluene (10 mL) and cooled to -30°C. Red-AI (3.5M in toluene, 1.64 mL, 5.73 mmol, 1.5 eq.) is added via a dropping funnel; the latter is further rinsed with toluene (5 mL), which is added to the reaction mixture. The solution is stirred at -20°C for 4h, then quenched at 0°C with a 10% aqueous solution of NaHSθ4 (100 mL). The aqueous layer is extracted with AcOEt (3 x 50 mL). The combined extracts are washed with brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hept : AcOEt, 6:1) affords a colourless oil.
20 Rf 0.59 (10% AcOEt / Hex); [α] D -16.2 (c 1, CHCI3); IR (thin film) : 2956 (s), 2911 (s), 2877
(s) (CH); 1726 (s, C=0); 1613 (m), 1514 (s, Bz); 1248 (s, Bz-O); 1096 (s), 1036 (s), 1011 (m,
Si-0 + C-O); 821 (m, arom CH); 741 (s, Si-C); 1H NMR (400MHz, CDCI3) δH: 9.69 (1H, d, J
= 0.9 Hz, CHO); 7.24 (2H, d, J = 8.7 Hz, PMB); 6.87 (2H, d, J = 8.7 Hz, PMB); 4.39 (2H, dd, J = 20.3, 11.6 Hz, PMB); 4.20 (1H, dd, J = 6.7, 3.7 Hz, H3); 3.77 (3H, s, PMB -OMe); 3.44
(1H, dd, J = 9.0, 5.3 Hz, H5A); 3.33 (1H, dd, J = 9.0, 6.0 Hz, H5B); 1.95 (1H, ddq, J = 7.0, 3.7, 0.9 Hz, H2); 1.94 (1H, m, H4); 1.09 ( 3H, d, J = 4.8 Hz, Me2); 0.95 (3H, d, J = 6.8 Hz, Me4); 0.93 (9H, t, J = 7.8 Hz, Si(CH2CH3)3); 0.55 (6H, q, J = 7.8 Hz, Si(CH2CH3)3) ; 13C NMR (100 MHz, CDCI3) δc : 204.8, 159.1, 130.5, 129.2, 113.6, 72.6, 71.6, 55.2, 49.9, 38.1,
14.2, 7.9, 6.9, 5.2; m/z (ES+) 403.3 (52, [M+Naj+); HRMS (ES+) calcd for C2iH3604SiNa [M+Na]+ 403.2281 , found 403.2261.
Stage 24.4 (2R 3S. 4S)- 3-triethylsilyloxy-5-(4-methoxybenzyloxy)-2.4-dimethyl-pentanoic acid
Aldehyde of stage 24.3 (795 mg, 2.09 mmol) is dissolved in t-BuOH (10 mL) and 2-methyl-2- butene (1 mL), and cooled to 0°C. A solution of sodium chlorite (80%, 473 mg, 4.18 mmol, 2 eq.), sodium dihydrogen phosphate (1.50 g, 12.53 mmol, 6 eq.) in H2O (10 mL) is added dropwise, the reaction mixture is allowed to warm up to RT, and stirred for 1 h. It is then diluted with H2O (200 mL). The aqueous layer is extracted with AcOEt (5 x 50 mL). The combined organic extracts are dried (Na2Sθ4) and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (hex : AcOEt 5:1) affords a colourless oil.
20 Rf 0.42 (25% AcOEt / Hex); [α] D -14 .1(c 0.66, CHCI3); IR (thin film) : 2956 (s), 2911 (s),
2877 (s) (CH); 2838 (m, O-CH3); 2637 (br w, COOH); 1707 (s, C=0); 1613 (m), 1587 (w), 1514 (s) (Bz); 1248 (s, Bz-O); 1093 (s), 1040 (s), 1011 (s, Si-O, C-O); 820 (m, arom CH); 741 (s, Si-C); 1 H NMR (400MHz, CDCI3) δH : 7.25 (2H, d, J - 8.7 Hz, PMB); 6.87 (2H, d, J =
8.7 Hz, PMB); 4.44 (1 H, d, J = 11.8 Hz, PMB); 4.41 (1 H, d, J = 11.8 Hz, PMB); 4.00 (1 H, m, H3); 3.80 (3H, s, PMB-OMe); 3.55 (1H, dd, J = 9.0, 5.6 Hz, H5A); 3.28 (1 H, dd, J = 9.0, 6.4 Hz, H5B); 2.69 (1H, dq, J = 7.0, 5.3 Hz, H2); 1.95 (1H, m, H4); 1.09 (3H, d, J = 7.0 Hz, Me2); 0.97 (3H, d, J = 6.9 Hz, Me4); 0.94 (9H, t, J = 7.8 Hz, Si(CH2CH3)3); 0.60 (6H, q, J = 7.8
Hz, Si (CH2CH3)3); 3C NMR (100 MHz, CDCI3) δC : 181.1, 159.0, 130.4, 129.1, 113.6,
75.1, 72.6, 71.7, 55.1, 43.2, 38.2, 14.6, 11.1, 6.9, 5.2; m/z (ES+): 419.2 (100, [M+Na]+); HRMS (ES+) calcd for C2ιH3605SiNa [M+Na]+ 419.2230, found 419.2264.
Stage 24.5: Methyl (2R,3S,4S)-3-triethylsilyloxy-5-(4-methoxybenzyloxy)-2,4-dimethyl- pentanoate
Acid of stage 24.4 (830 mg, 2.09 mmol) is dissolved in DMF (5 mL). At RT potassium carbonate (433 mg, 3.135 mmol, 1.5 eq.) is added, followed by methyl iodide (0.195 mL,
3.135 mL, 1.5 eq.). The reaction mixture is stirred at RT for1 h, before being diluted with brine (200 mL). The aqueous layer is extracted with AcOEt (5 x 50 mL). The combined organic extracts are dried (Na2Sθ4) and concentrated under vacuum. Purification by flash chromatography on silica gel (Hex : AcOEt, 8:1 to 1:1) affords a colourless oil. Rf 0.69 (20%
20 AcOEt / Hex); [α] p - 13.1 (c 1, CHCI3); IR (thin film): 2953 (s), 2912 (m), 2877 (m) (CH);
1739 (s, C=0); 1613 (m), 1514 (s) (Bz); 1248 (s, C-O); 1085 (s), 741 (s) (Si-C); 1H NMR (400MHz, CDCI3) δH : 7.26 (2H, d, J = 8.7 Hz, PMB); 6.86 (2H, d, J = 8.7 Hz, PMB); 4.43 (1H, d, J = 11.6 Hz, PMB); 4.39 (1H, d, J = 11.6 Hz, PMB); 4.04 (1H, dd, J = 6.4, 4.7 Hz, H3); 3.80 (3H, s, PMB-OMe); 3.65 (3H, s, OMe-ester); 3.50 (1H, dd, J = 9.0, 4.5 Hz, H5A); 3.26 (1H, dd, J = 9.0, 7.2 Hz, H5B); 2.64 (1H, dq, J = 7.0, 4.7 Hz, H2); 1.87 (1H, m, H4); 1.13 (3H, d, J = 7.0 Hz, Me2); 0.96 (3H, d, J = 6.9 Hz, Me4); 0.92 (9H, t, J = 8.0 Hz, Si(CH CH3)3); 0.55 (6H, q, J = 8.0 Hz, Si(CH2CH3)3); 13C NMR (100 MHz, CDCI3) δς : 175.7, 159.0, 130.7, 129.1, 113.6, 75.0, 72.6, 71.9, 55.2, 51.5, 42.9, 38.4, 14.5, 11.2, 6.9, 5.2; m / z (ES+): 433 (100, [M+Na]+); m/z (ES+) 433.24 (100, [M+Na]+); HRMS (ES+) calcd for C22H38θ5SiNa [M+Na]+ 433.2386, found 433.2397.
Stage 24.6: Methyl (2R3S,4S)-3-triethylsilyloxy-2,4-dimethyl-5-hvdroxy-pentanoate Ester of stage 24.5 (30 mg, 0.073 mmol) is dissolved in DCM (2 mL). pH 7 buffer (0.2 mL) is added, and the solution is cooled to 0°C. DDQ (20 mg, 0.088 mmol, 1.2 eq.) is added slowly, and the reaction mixture is stirred for 1 h at 0°C. pH 7 buffer (20 mL) is added to the mixture, and it is extracted with AcOEt (5 x 10 mL). The combined organic extracts are dried over Na2Sθ4 and concentrated under vacuum. Purification by flash chromatography on silica gel
(20% Et2θ in PE) affords a colourless oil.
Rf 0.27 (20% AcOEt / Hex); [α]2p -2.6 (c 1, CHCI3); IR (thin film) : 3453 (br, OH), 2955 (s), 2911 (s), 2879 (s) (CH), 1738 (s, C=0), 1458 (m), 1201 (m), 1092 (s), 1056 (s), 1011 (s, Si- O + C-O), 740 (s, Si-C); 1H NMR (400MHz, CDCI3) δH: 4.04 (1H, dd, J = 5.5, 5.5 Hz, H3); 3.68 (3H, s, OMe); 3.67 - 3.45 (2H, m, H5); 2.66 (1H, m, H2); 2.32 (1H, m, OH); 1.75 (1H, , H4); 1.19 ( 3H, d, J = 7.1 Hz, Me2); 1.00 - 0.90 (12H, m, Me4 + Si(CH2CH3)3); 0.63 (6H, q, J = 7.9 Hz, Si(CH2CH3)3); 13c NMR (100 MHz, CDCI3) δC : 175.8, 77.2, 65.3, 51.7,
43.6, 39.5, 14.5, 12.4, 6.9, 5.1; m/z (ES+) 313.18 (100, [M+Na]+); HRMS (ES+) calcd for C14H3oθ4SiNa [M+Na]+ 313.1811, found 313.1799.
Example 25: 11. 17-bis-(t-butyldimethylsilyl)-3-triethylsilyl-7-oxo-discodermolide
Aldol adduct of step 25.1 (90 mg, 0.093 mmol) is dissolved in THF (1 mL), water (1 mL) and AcOH (1 mL). The reaction mixture was stirred at RT for 3 days, before being quenched with saturated aqueous NaHC03 (20 mL). The aqueous layer is extracted with AcOEt (5 x 10 mL). The combined extracts are dried (Na2S04) and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hex:AcOEt, 6:1) affords the title compound, along with some recovered starting material . Rf 0.56 (33% AcOEt / Hex); [α]2p +75.0 (c 0.1, CHCI3); IR (thin film) : 3600 - 3200 (w, NH);
2958 (s), 2931 (s), 2880 (s), 2857 (m) (CH); 1725 (s, C=0); 1610 (w, NH2); 1252 (m, Si- CH3); 1096 (s), 1037 (s) (Si-0 + C-O); 836 (s), 774 (s) (Si-C + Si-CH3); 1H NMR (400MHz, CDCI3) δH : 6.59 (1H, ddd, J = 16.9, 10.7, 10.4 Hz, H23); 6.25 (1H, dd, J = 11.5, 9.5 Hz, H9); 6.09 (1 H, d, J = 11.6 Hz, H8); 5.03 (1 H, dd, J = 11.0, 11.0 Hz, H22); 5.38 (1 H, dd, J =
10.6, 10.4 Hz, H21); 5.21 (1H, dd, J = 16.8, 1.5 Hz, H24trans); 5.13 (1H, br d, J = 10.2 Hz, H24cis); 4.84 (1H, d, J = 10.3 Hz, H13); 4.81 -4.75 (1H, m, H5); 4.73 (1H, dd, J = 6.1, 6.1 Hz, H19); 4.68 (2H, br s, NH2); 3.68 (1H, dd, J = 3.4, 2.4 Hz, H3); 3.61 - 3.55 (1H, m, H10); 3.42 - 3.35 (2H, m, H11 + H17); 2.98 (1H, m, H20); 2.84 (1 H, dd, J = 16.2, 5.6 Hz, H6A); 2.70 (1H, dd, J = 16.2, 5.1 Hz, H6B); 2.62 (1H, dq, J = 7.5, 3.5 Hz, H2); 2.29 (1H, m, H12); 2.14 - 2.07 (1H, m, H4); 2.02 (1H, dd, J = 12.6, 12.3 Hz, H15A); 1.90 - 1.75 (2H, m, H16 + H18); 1.60 - 1.50 (1H, m, H15B); 1.56 (3H, s, Me14); 1.25 (3H, d, J = 7.5 Hz, Me2); 1.01 - 0.90 (39H, m, SΪCH2CH3 + SiC(CH3)3 + Me4 + Me10 + Me12 + Me20); 0.86 (3H, d, J = 6.7 Hz, Me18); 0.68 (3H, d, J = 6.6 Hz, Me16); 0.59 (6H, q, J = 8.0 Hz, Si(CH2CH3)3); 0.10 - 0.02 (12H, m, SiCH3); 13C NMR (100 MHz, CDCI3) δC : 196.8, 173.8, 157.1, 152.4, 133.7, 132.7, 132.1, 130.3, 129.7, 125.4, 117.9, 80.5, 78.7, 77.7, 77.2, 74.0, 46.9, 43.8, 38.1, 38.0,
37.7, 36.2, 34.9, 34.4, 33.6, 26.2 (2 signals), 22.7, 18.5, 18.4, 18.2, 16.0, 13.7, 13.5, 10.0, 6.8, 4.9, -3.4, -3.5 (2 signals), -3.8; m/z (ES+) : 956.2 (100, [M+Na]+); HRMS (ES+): calcd for C51H99N208Si3 [M+NH4J+ 951.6709, found 951.6701.
Stage 25.1: Methyl (2R 3S. AS. 5S. 8Z. 10S, 11S. 12S. 13Z. 16S. 17R. 18S. 19S. 20S. 21Z.V7, 11-bis(t-butyldimethylsilyloxy)-19-carbamoyloxy-3-triethylsilyloxy-5-hvdroxy-2. 4. 10. 12. 14. 16. 18. 20-octamethyl-7-oxotetracosa-8. 13. 21. 23-tetraenoate
A solution of the ketone of Example 19 (176 mg, 0.259 mg) is dissolved in Et20 (1 mL) and cooled to 0°C. c-Hex2BCI (1M in hexanes, 0.777 mL, 0.777 mmol, 3 eq.) is added, followed immediately by Et3N (0.119 mL, 0.855 mmol, 3.3 eq.), and the reaction mixture is stirred at 0°C for 40 min, before being cooled to -78°C, and stirred at that temperature for 10 min. (112 mg, 0.39 mmol, 1.5 eq.) of the freshly prepared product from example 24 is added in solution in Et20 (2 mL, which includes the washings), and the reaction mixture is stirred at - 78°C for 20 h. It is then quenched with pH 7 buffer (10 mL), and extracted with Et20 (2 x 5 mL). The ether extracts are diluted with MeCN (10 mL) and H2O (1 mL), and put on top of a column packed with reverse phase silica and MeCN:H2Q (98:2). Elution with MeCN:H20 (98:2) until all the by-products derived from the excess aldehyde and boron reagent are out, then MeCN, then a gradient of MeCN:TBME (98:2 to 80:20) which affords the title compound and a trace of its epimer at C5.
Rf 0.52 (33% AcOEt / Hex); [ ]2^ +40.0 (c 0.16, CHCI3); IR (thin film) : 3600 - 3300 (br w,
OH, NH2); 2958 (s), 2932 (s), 2880 (s) 2857 (s) (CH); 1732 (s, C=0 ester); 1720 - 1700 (s, C=0 ketone + carbamate); 1610 (w, NH2), 1253 (s, Si-CH3), 1093 (s), 1039 (s, Si-O-C + C- O); 836 (s), 774 (s, Si-C + Si-CH3); 1H NMR (400MHz, CDCI3) δH : 6.59 ( 1H, dd, J = 16.9, 10.7, 10.5 Hz, H23); 6.23 (1H, dd, J = 11.5, 8.6 Hz, H9); 6.04 (1H, d, J = 11.6 Hz, H8); 6.02 (1H, dd, J = 11.1, 11.0 Hz, H22); 5.37 (1H, dd, J = 10.5, 10.5 Hz, H21); 5.21 (1 H, dd, J = 16.8, 1.6 Hz, H24trans); 5.12 (1H, br d, J = 10.2 Hz, H24cis); 4.84 (1H, br d, J = 10.3 Hz, H13); 4.73 ( 1H, dd, J = 6.0, 6.0 Hz, H19); 4.70 (2H, br s, NH2); 4.14 (1H, dd, J = 5.5, 5.4 Hz, H3); 4.04 (1H, m, H5); 3.67 (3H, s, OMe); 3.58 (1H, m, H10); 3.51 (1H, m, OH); 3.40 - 3.30 (2H, m, H11 + H17); 2.98 (1H, ddq, J = 10.0, 6.6, 6.3 Hz, H20); 2.70 - 2.60 (2H, m, H6A + H2); 2.46 (1H, dd, J = 17.2, 9.0 Hz, H6B); 2.30 (1H, ddq, J = 10.0, 7.3, 6.4 Hz; H12); 2.01 (1H, dd, J = 12.6, 12.3, H15A); 1.90 - 1.75 (3H, m, H4 + H16 + H18); 1.60 - 1.56 (1H, m, H15B); 1.55 (3H, s, Me14); 1.15 (3H, d, J = 7.0 Hz, Me2); 0.99 - 0.83 (42H, m, SiCH2CH3 + Me10 + Me20 + Me4 + Me12 + Me18 + Si(CH3)3); 0.67 (3H, d, J = 6.7 Hz, Me16); 0.57 (6H, q, J = 8.0 Hz, SiCH2CH3); 0.10 - 0.01 (12H, m, Si-CH3); 13C NMR (100 MHz, CDCI3) δC : 200.8, 176.2, 157.1, 152.0, 133.6, 132.7, 132.0, 130.2, 129.7, 125.5, 117.9, 80.4, 78.6, 74.6, 68.6, 51.7, 47.4, 43.6, 42.8, 38.1, 38.0, 37.7, 36.2, 34.8, 34.4, 26.2 (2 x C), 22.7, 18.5, 18.4, 18.2, 17.6, 17.5, 13.7, 12.2, 11.9, 10.1, 6.9, 5.2, -3.4, -3.5 (2 x C), - 3.9; m/z (ES+) 988.65 (100, [M+Na]+); HRMS (ES+) calcd for C52H99N09Si3Na [M+Na]+ 988.6525, found 988.6552.
Example 26: (3Z.8Z.16ZH5S.7S.11 S.13R.15S)-6(S).12(R)-Bis-(.tert.-butyl-dimethyl- silanyloxy)-14(S)-hvdroxy-5.7.9.11,13.15-hexamethyl-nonadeca-3.8,16.18-tetraen-2-one
A solution of 6.7g (10.52mMol) of the acid of stage 24 is dissolved in 80mL of diethyl ether and cooled to an internal temperature of -20°C. Maintaining the internal temperature between -20°C and -10°C 23.1 mL of a 5% solution of methyl lithium in diethyl ether is added slowly within a period of 30 min. The reaction mixture is warmed to 0°C and stirred at that temperature overnight. After this time the pH of the reaction mixture is adjusted to between 3 and 4 with a 10% aqu. solution of citric acid. The organic phase is separated, washed with water and dried with sodium sulphate. The suspension is filtered and the solvent removed in vacuum to deliver the crude product as colourless oil. Chromatographic purification on silica- gel, eluting with a mixture of ethyl acetate/heptane (1/10) affords the pure ketone; 1H-NMR, d6-DMSO (δ), 6.60(1 H, dt, CH=), 6.15-6.08(2H, m, CH=), 6.00(1H, pseudo t, CH=), 5.55(1H, pseudo t, CH=), 5.20(1 H, d, CH=), 5.10(1 H, d, CH=), 4.95(1 H, d, CH=), 4.10 - 3.95(1 H, Brs, exch. D20, OH), 3.60 - 3.45(3H, m, 2 x CHOSi + CH(CH3)C=), 3.31 (1H, m, CHOH), 2.80(1 H, m, CH(CH3)C=), 2.38(1 H, m, CH(CH3)C=), 2.15 - 2.05(4H, m, ketone CH3 + CH), 1.80(1 H, m, CHCH3), 1.75 - 1.60(2H, m, 2 x CH), 1.55(3H, s, CH3C=), 1.00- 0.85 (30H, m, 2 x t-Bu + 4 x CH3), 0.70(3H, d, CH3), 0.08(12H, s, Me2Si).
Stage 26.1: (2Z,7Z,15Z)-(4S,6S,10S,12R, 14S)-5(S),11(R)-Bis-(.tert.-butyl-dimethyl- silanyloxy)-13(S)-hydroxy-4,6,8,10,12,14-hexamethyl-octadeca-2,7,15,17-tetraenoic acid A solution of 10g (15.36mMol) of (2Z.7Z, 15Z)-(4S,6S, 10S, 12R, 14S)-5(S), 11 (R)-Bis-(.tert.- butyl-dimethyl-silanyloxy)-13(S)-hydroxy-4,6,8,10,12,14-hexamethyl-octadeca-2,7,15,17- tetraenoic acid methyl ester is dissolved in 100mL of methanol. Within 5 min 8.2mL of a 30% aqueous solution of sodium hydroxide is added. The resulting mixture is heated to reflux temperature and stirred at this temperature overnight. The mixture is then cooled to RT and 50mL of water and 50mL of methylene chloride is added. The organic phase is separated and the pH adjusted to 3 with a 2.0M solution of hydrochloric acid. The organic phase is separated and dried by the addition of magnesium sulphate. The suspension is filtered and the solvent removed under reduced pressure to give the product as a foam; 1 H-NMR, d6- DMSO (δ), 12.20-11.90(1 H, Brs, exch D2O, C02H), 6.61 (1H, dt, CH=), 6.22(1 H, dd, CH=), 6.00(1 H, t, CH=), 5.65(1 H, d, CH=), 5.50(1 H, t, CH=), 5.20(1 H, d, CH=), 5.10(1 H, t, CH=), 5.10(1H, d, CH=), 4.85(1H, d, CH=), 4.40(1H, d, exch D20, OH), 3.60(1H, m, CHOSi), 3.50(1 H, m, CHOSi), 3.29(1 H, m, CHOH), 3.10(1 H, m, CHC=), 2.80(1 H, m, CH), 2.35(1 H, m, CH), 1.70(1H, m, CH), 1.60(1H, m, CH), 1.54(3H, s, Me), 1.00-0.90(30H, m), 0.65(3H, d, CH3), 0.05(12H, s, Me2Si).
Example 27: (3Z. 5S. 6S. 7R 8S. 9R. 11Z, 13S. 14R 15S)-14-(t-Butyldimethylsilyloxy)-6.16- bis-(o-methoxybenzyloxy)-9-(hvdroxymethyl)-5,7,11 ,13,15-pentamethyl-hexadeca-1 , 3,11- trien-8-ol To a stirred solution of aldol adduct from stage 27.3 (58 mg, 65 μmol) in THF (2 mL) at -78°C is added LiAIH4 (333 μL of a 1.17M/THF solution, 389 μmol). The reaction mixture is stirred at - 78°C for 1 hr and then allowed to gradually warm to 0°C over 1 hr. The reaction is quenched by the careful addition of potassium sodium tartrate (3 mL) and stirred vigorously at RT. After 30 min, the layers are separated and the aqueous layer is extracted with Et2θ (3 x 5 mL). The combined organics are dried (Na2Sθ4) and concentrated in vacuo. Flash chromatography (30% on
EtOAc/Hexanes) gives diol as a white foam: Rf 0.13 (25% EtOAc/Hexane); [α] +34.1 (c 0.60, CHCI3); IR (Thin film) 3416 (m br, OH), 2959 (s), 2856 (s), 1613 (s), 1586 (w), 1514 (s), 1462 (s), 1249 (s); 1H NMR (500 MHz, CDCI3) δH 7.26-7.21 (4H, m, ArH), 6.90-6.82 (4H, m, ArH), 6.68 (1H, ddd, J = 16.7, 10.7, 10.6 Hz, H23), 6.07 (1H, dd, J = 11.0, 10.9 Hz, H22), 5.50 (1H, dd, J = 10.5, 10.4 Hz, H21), 5.24 (1H, d, J = 16.6 Hz, H24A), 5.15 (1H, d, J = 10.3 Hz, H24B). 5.04 (1H, d, J = 10.0 Hz, H13), 4.70 (1H, d, J = 10.2 Hz, CHAHBAΓ), 4.43-4.35 (3H, m, CJHAHBAΓ + Qi2Ar), 3.81-3.77 (1H, mo s, OH), 3.79 (6H, s, 2 x OCH3), 3.69-3.63 (2H, m, H17 + H25A). 3.54-3.47 (2H, m, H9A + H 5B)> 3.39 (1H, dd, J = 6.3, 4.4 Hz, Hig), 3.36 (1H, dd, J = 5.6, 4.5, Hz, H11), 3.32 (1H, dd, J = 7.4, 3.1 Hz, OH), 3.20 (1H, dd, J = 8.7, 8.3 Hz, HgB), 3.07 (1H, ddq, J = 9.8, 6.9, 6.8 Hz, H2o), 2.54-2.45 (1H, m, H12), 2.01-1.91 (2H, m, H10 + HI5A), 1.91-1.83 (2H, m, H16 + Hι8), 1.65-1.60 (1H, mo s, Hι5B), 1.62 (3H, s, Meι4), 1.03 (3H, d, J = 6.9 Hz, Me2o), 1.01 (3H, d, J = 7.0 Hz, Meι8), 0.94 (3H, d, J = 7.0 Hz, Mβιo), 0.91-0.87 (12H, m, Meι2 + SiC(CH3)3), 0.02 (6H, s, Si(CH3)2); 13C NMR (100 MHz, CDCI3) δc 159.4, 159.1, 135.0, 132.3 (3C), 130.8, 130.1, 129.7, 129.6, 129.2, 118.0, 113.8, 113.7, 87.7, 79.9, 78.7, 74.3, 72.7, 72.6, 65.4, 55.3 (2C), 40.3, 38.3, 36.9, 35.9, 35.5, 30.8, 26.2, 23.4, 18.4, 18.1, 17.0, 15.1, 7.0, -
3.8, -3.9; m/z (ES+) 761 (100, [M+Na]+); HRMS (ES+) calcd for C44H70O7SiNa [M+Na]+ 761.4789, found 761.4767.
Stage 27.1: 4-Methoxy-2.6-Dimethylphenol
To a stirred solution of 2,6-dimethylbenzoquinone (ca. 170mg, 1.37 mmol) in acetic acid (1.3ml, 60% aq. solution) is added Zn powder (253 mg, 3.87 mmol). The mixture is heated at reflux for 2 hours, before cooling to RT. The solutin was then filtered, extracted with ET20 (3 x 5 ml) and the combined organic extracts are dried over MgS04 and concentrated in vacuo. The resulting residue is dissolved in MeOH (1 ml) before the addition of cone. H2SO (0.2ml). The mixture is heated to reflux for 1 hour and then poured over ice(10g). The organic products are extracted with ET2O (3x20ml), dried over MgS04 and concentrated in vacuo. Flash chromatography (20% ETOAc/Hexanes) gives the title compound as a white solid.Fp 75-76°C; 1H NMR (400MHz, CDCI3) δH 6.50(2H, s, ArH), 4.20 ( 1H, s, OH), 3.79 (3H, s, OCH3) 2.25 (6H, s, 2xArCH3).
Stage 27.2: 4-methoxy-2,6-dimethylphenyl acetate
To a solution of 4-Methoxy-2,6-Dimethylphenol from stage 27.1 (29mg, 0.19 mmol) in CH2CI2 (1.0 ml) at 0°C are added ET3N (27mL, 0.19 mmol) and acetyl chloride (16 ml, 0.23 mmol, 1.2 eq.). The reaction mixture is quenched by the addition of sat. aq. NH CI (2ml). The organic products are extracted into CH2CI2 (3x5ml), dried over MgSO4 and concentrated in vacuo. Flash chromatography (20% EtOAc/Hexanes) gives 4-methoxy-2,6-dimethylphenyl acetate as a white solid. 1H NMR (400 NHz, CDCI3) δH 6.58 (2H, s, ArH), 3.75 (3H, s, OCH3), 2.30 (3H, s, CH3COOAr), 2.11 (6H, s, 2xArCH3).
Stage 27.3: (4-Methoxy-2.6-Dimethylphenyl) (2S. 3S. 4S, 5S, 6S, 7Z)-2-lT2Z, 4S, 5R. 6S)-5- (t-butyldimethylsilyloxy)-7-(p-methoxybenzyloxy)-2,4,6-trimethyl-hept-2-enyll-3-hvdroxy-5-(p- methoxybenzyloxy)-4,6-dimethyl-deca-7.9-dienoate
To a stirred solution of 480mg (801 μmol, 1.15 eq.) of 4-methoxy-2, 6-dimethylphenyl (4Z, 6S, 7R, 8S)-7-(t-butyldimethylsilyloxy)-9-(p-methoxybenzyloxy)-4,6,8-trimethyl-4-nonenoate (prepared according to I. Paterson, G. Florence, et al, J. Am. Chem. Soc. 2001, 123, 9535- 9544) in THF (2.5 mL) at -100°C is added freshly prepared LiTMP (4.63 mL of ca. 0.26 M/THF solution, 1.0 mmol, 1.43 eq.). After 30 min at -100°C, a precooled (-100°C) solution of 196 mg (698 μmol) of aldehyde (Z)-(2S, 3S, 4S)-3-(p-Methoxybenzyloxy)-2,4-dimethyl- octa-5,7-dienal (prepared according to I. Paterson, G. Florence, et al, J. Am. Chem. Soc. 2001 , 123, 9535-9544 or J. Nerenberg et al, J. Am. Chem. Soc. 1993, 115, 12621-12622) in THF (0.5 mL) is added via cannula. After 30 min at -100°C the reaction is mixture is canulated into a solution of CSA (232.2mg, LOmmol) in THF (10ml) at -78°C and stirred for 15 minutes. After warming to RT, NH4CI (20 mL) is added, the layers are separated and the aqueous layer is extracted with Et20 (3 x 25 mL). The combined organics are dried (MgS04) and concentrated in vacuo . Flash chromatography (10-30% EtOAc/Hexanes) gives recovered aryl ester and the desired aldol product as a viscous colourless oil; Rf 0.40 (35 % EtOAc/Hexane); [α]2^ +31.9 (c 1.3, CHCI3); IR (Thin film) 3480 (m br, OH), 2942 (s),
2923 (s), 2845 (s), 1748 (s), 1586 (w), 1514 (s), 1463 (s), 1248 (s); 1H NMR (500 MHz, CDCI3) δH 7.26-7.22 (4H, m, AΓHP B). 6.87-6.83 (3H, m, AΓHDMP)- 6.90-6.80 (4H, m, ArHpMB). 6.68 (1H, ddd, J = 16.8, 10.6, 10.6 Hz, H23), 6.56 (2H, s, AΓHMDMB), 6.08 (1H, dd, J = 10.9, 10.9 Hz, H22), 5.52 (1H, dd, J = 10.5, 10.4 Hz, H21), 5.22 (1H, d, J = 16.8 Hz, H24A), 5.16 (1H, d, J = 10.2 Hz, H24B). 5.08 (1H, d, J = 9.8 Hz, H13), 4.70 (1H, d, J = 10.2 Hz, CJHAHBAΓPMB). 4.42-4.36 (3H, m, CHAHBAΓPMB +
Figure imgf000092_0001
8.9 Hz, H17), 3.79 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.49 (1H, dd, J = 9.1 , 4.8 Hz, HgA), 3.45 (1H, app t, J = 4.9 Hz, Hig), 3.37 (1H, app t, J = 5.1 Hz, Hn), 3.22-3.17 (2H, m, HgB + OH), 3.11-3.07 (2H, m, Hi6 +H20), 2.70-2.63 (2H, m , H12 + H15A). 2.09 (6H, s, ArMDMB(CH3)2), 1.99-1.91 (2H, m, H10 + Hι8), 1.83 (1H, dd, J = 13.9, 3.4 Hz, Hι5B), 1.78 (3H, s, Me ), 1.05 (6H, app d, J = 6.8 Hz, Meι8 + Me2o), 0.94 (3H, d, J = 6.9 Hz, Meιn), 0.87 (9H, s, SiC(CH3)3), 0.79 (3H, d, J = 6.5 Hz, Meι2), 0.01 (3H, s, SiCH.3), 0.00 (3H, s, SiCH3). 13C NMR (100 MHz, CDCI3) δC 173.3, 159.3, 159.0, 156.7, 142.1, 134.7, 133.8, 132.2, 130.9, 130.0, 129.9, 129.7, 129.4, 129.1, 128.7, 113.9, 113.8, 113.7, 113.5, 87.4, 78.6, 76.0, 74.6, 72.6, 55.3 (3C), 47.8, 38.2, 36.6, 35.7, 35.6, 29.7, 29.7, 26.1, 24.7, 23.1, 18.4, 18.2, 17.0,
16.5, 15.0, 6.8, -3.9 (2C); m/z (ES+) 905 (100, [M+NH4]+), 887 (25), 579 (23), 142 (48); HRMS (ES+) calcd for C53H820gSiN [M+NH4]+ 904.5759, found 904.5756.
Example 28: Methyl (2R. 3S. 4S. 5S, 8Z. 10S, 11S, 12S, 13Z. 16S, 17R 18S. 19S. 20S. 21Z,)-3,7,11-tris(t-butyldimethylsilyloxy)-19-carbamoyloxy-5-hydroxy-2. 4, 10. 12. 14. 16. 18. 20-octamethyl-7-oxotetracosa-8, 13. 21. 23-tetraenoate.
To a solution of ketone 19 (353 mg, 0.52 mmol) in Et2θ (1.5 ml), at 0°C, is added cHex2BCI (1M solution in hexanes, 1.56 ml, 1.56 mmol, 3 eq) and immediately afterwards triethylamine (240 μl, 1.716 mmol, 3.2 eq). After 30 min enolisation at 0"C, the reaction mixture is cooled at -78°C and stirred for 10 min. Aldehyde from stage 24 (270 mg, 0.937 mmol, 1.8 eq.) is added in 0.4 ml of Et2θ. The flasks containing the aldehyde is rinsed twice with 0.4 mL Et2θ, and these washings are added to the reaction mixture. After stirring at - 78°C for 2 h, the reaction mixture is quenched by the addition of pH7 buffer (3 mL), and allowed to warm up to 0°C. After extraction with Et2θ (2 x 5 mL), the combined organic extracts are diluted with MeCN (20 mL) and H2O (5 mL) and put straight on top of a column packed with reverse phase silica (eluent : MeCN/H2θ, 98:2). MeCN/^O is passed through the column to get rid of the by-products derived from the excess aldehyde and cHex2BCI.
The solvent is then switched to neat MeCN, and then a gradient of MeCN/TBME (98:2 to 80:20). This gives Methyl (2R, 3S, AS, 5S, 8Z, 10S, 11S, 12S, 13Z, 16S, 17R, 18S, 19S, 20S, 21Z,)-3,7,11-tris(t-butyIdimethylsilyloxy)-19-carbamoyloxy-5-hydroxy-2, 4, 10, 12, 14, 16, 18, 20-octamethyl-7-oxotetracosa-8, 13, 21, 23-tetraenoate together with its epimer at
C5. Rf: 0.5 (33% EtOAc / hexane); [α]2^ +58.6 (c 2.2, CHCI3); IR (Thin film) 3513 (m, OH, NH2), 2957 (s), 2930 (s), 2885 (s), 2857 (s), 1731(s, C=0), 1607 (m), 1472 (s), 1462 (s), 1387 (s), 1362 (s), 1327 (s), 1255 (s); 1H NMR (400 MHz, CDCI3) δH 6.60 (1H, ddd, J = 16.8, 10.9, 10.3 Hz, H23), 6.26 (1H, dd, J = 11.5, 9.5 Hz, Hg), 6.04 (1H, d, J = 11.6 Hz, H8),
6.02 (1H, dd, J = 11.1, 11.0 Hz, H22), 5.38 (1H, dd, J = 10.5, 10.4 Hz, H21), 5.22 (1H, dd, J = 16.8, 1.7 Hz, H24trans)> 5.14 (1H, d br, J = 10.1 Hz, H24cis). 4.84 (1H, d br, J = 10.4 Hz, H13), 4.74 (1H, dd, J = 6.0, 6.0 Hz, H19), 4.60 (2H, s br, NH2), 4.21 (1H, dd, J = 5.2, 5.2 Hz, H3), 4.03 (1H, m, H5), 3.68 (3H, s, OMe), 3.60 (1H, m, H10), 3.53 (1H, d, J = 3.0 Hz, OH), 3.40 - 3.35 (2H, m, Hn + H17), 2.98 (1H, ddq, J = 10.1, 6.6, 6.6 Hz, H2o), 2.72 - 2.62 (2H, m, H6 + H2), 2.47 (1H, dd, J = 17.3, 9.0 Hz, H6), 2.31 (1H, ddq, J = 10.0, 7.1, 7.1 Hz, H12),
2.03 (1H, dd, J = 12.4, 12.2 Hz, H15), 1.91 - 1.79 (3H, m, H4 + H16 + His), 1.61 - 1.59 (1H, m, H15), 1.57 (3H, s, Meι ), 1.15 (3H, d, J = 7.1 Hz, Me2), 1.01 - 0.96 (6H, 2xd, J = 6.8 + 7.0 Hz, Mein + Me2o), 0.94 - 0.82 (36H, m, Mβ4 + Meι2 + Meι8 + SiC(CH3)3), 0.69 (3H, d, J = 6.7 Hz, Mei6), 0.15 - 0.00 (18H, m, SiCH3); 13C NMR (100 MHz, CDCI3) δC 200.8, 176.2, 157.0, 152.1 , 133.6, 132.7, 132.1 , 130.3, 129.7, 125.4, 117.9, 80.5, 78.6, 77.0, 73.7,
68.6, 51.7, 47.5, 43.9, 42.5, 38.1 (2C), 37.7, 36.2, 34.8, 34.4, 26.2 (2C), 25.9, 18.5, 18.4,
22.7, 18.2, 17.6, 17.5, 13.6, 12.3, 11.6, 10.1, -3.4, -3.5 (2C), -3.8, -4.4, -4.5; HRMS (ES+) Calcd for C52HggOgNιSi3Na [M+Na]+ 988.6520, Found: 988.6587.

Claims

WHAT IS CLAIMED IS:
1. A process for preparing a lactone of formula
Figure imgf000094_0001
wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group and R is H2NC(O)-, in which process in a first step a triene of formula V
Figure imgf000094_0002
wherein
Rι> R2. R3 and R4 are protecting groups for a hydroxy group, characterized in that Ri and R* can be split off under reaction conditions that do not result in cleavage of any of the protecting groups R2 or R3, is prepared by the reaction of a vinyl iodide of formula VI,
Figure imgf000095_0001
wherein Ri and R2 are different protecting groups for a hydroxy group, characterized in that Ri can be split off under reaction conditions that do not result in the cleavage of the protecting group R2, with a diene of formula VII,
Figure imgf000095_0002
wherein R3 and R are different protecting groups for a hydroxy group and X is a leaving group, characterized in that R4 can be split off under reaction conditions that do not result in the cleavage of the protecting group R3,
in a second step the protecting groups Ri and R4 are split off to provide a compound of formula V, wherein Ri and R4 are hydrogen, and R2 and R3 are identical or different protecting groups for a hydroxy group,
in a third step the only primary hydroxy group in the compound of formula V is selectively oxidized to provide an aldehyde of formula IX
Figure imgf000096_0001
wherein R4 is hydrogen, and R2 and R3 are identical or different protecting groups for a hydroxy group,
in a fourth step the aldehyde of formula IX is reacted with a phosphonate ester of formula X
OCH2CF3
OCH CF,
O O
(X)
furnishing a ketone of formula II
Figure imgf000096_0002
wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is hydrogen,
optionally, in a fifth step such ketone of formula II is reacted with CI3C(0)NCO in the presence of neutral Al203 to provide a ketone of formula II,
Figure imgf000097_0001
wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is H2NC(0)-,
in a sixth step an aldol coupling reaction is conducted of said ketone of formula II with an aldehyde of formula III
Figure imgf000097_0002
wherein
R5 is a protecting group for a hydroxy group, and
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia
wherein R9 represents alkyl or aryl, Ri0 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the aldehyde of formula III via the nitrogen atom, to provide a tetraene of formula IV
Figure imgf000098_0001
wherein
R2, R3 and R5 are identical or different protecting groups for a hydroxy group,
R4 is hydrogen or H2NC(0)-,
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia wherein R9 represents alkyl or aryl, Rι0 and R represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom,
wherein the tetraene of formula IV wherein R4 is H2NC(0)- subsequently is the subject of a diastereoselective reduction followed by a lactonization reaction, or of a lactonization reaction followed by a diastereoselective reduction, to provide the lactone of formula I, wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group, or
wherein the tetraene of formula IV wherein R4 is hydrogen, subsequently is the subject of a lactonization reaction followed by a reaction installing the carbamate and a diastereo- selective reduction, to provide the lactone of formula I, wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group and R4 is H2NC(0)-.
2. A process for preparing a triene of formula V
Figure imgf000099_0001
wherein
Ri and Rt are hydrogen, and
R2 and R3 are identical or different protecting groups for a hydroxy group, in which process a vinyl iodide of formula VI,
Figure imgf000099_0002
wherein Ri and R2 are different protecting groups for a hydroxy group, characterized in that Ri can be split off under reaction conditions that do not result in the cleavage of the protecting group R2, is reacted with a diene of formula VII,
Figure imgf000100_0001
wherein R3 and R are different protecting groups for a hydroxy group and X is a leaving group, characterized in that R can be split off under reaction conditions that do not result in the cleavage of the protecting group R3, and wherein afterwards, the protecting groups Ri and R are split off simultaneously or sequentially.
3. A vinyl iodide of formula VI
Figure imgf000100_0002
wherein R^ and R2 are different protecting groups for a hydroxy group, characterized in that R can be split off under reaction conditions that do not result in the cleavage of the protecting group R2, or a salt thereof, if applicable.
4. A vinyl iodide of formula VI according to claim 3, wherein Ri is triethylsilyl and R2 is tert- butyl-dimethyl-silyl.
5. A diene of formula VII,
Figure imgf000101_0001
wherein R3 and R4 are different protecting groups for a hydroxy group and X is a leaving group, characterized in that ( can be split off under reaction conditions that do not result in the cleavage of the protecting group R3, or a salt thereof, if applicable.
6. A diene of formula VII according to claim 5, wherein R4 is triethylsilyl and R3 is tert-butyl- dimethyl-silyl.
7. A process for preparing a tetraene of formula IV
Figure imgf000101_0002
wherein
R2, R3 and R5 are identical or different protecting groups for a hydroxy group,
R4 is hydrogen or H2NC(0)-,
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or (c) a substructure of formula Ilia
Figure imgf000102_0001
wherein R9 represents alkyl or aryl, Rι0 and R represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom, in which process a ketone of formula II
Figure imgf000102_0002
wherein R2 and R3 are identical or different protecting groups for a hydroxy group,
F^t is hydrogen or H2NC(0)-, is reacted with an aldehyde of formula III
Figure imgf000102_0003
wherein
R5 is a protecting group for a hydroxy group, and R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia wherein R9 represents alkyl or aryl, Rio and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the aldehyde of formula III via the nitrogen atom, and wherein, optionally, afterwards, the groups R, R2 R3 and R5 are split off simultaneously or sequentially.
8. A tetraene of formula IV
Figure imgf000103_0001
wherein
R2, R3 and R5 are identical or different protecting groups for a hydroxy group,
R is hydrogen or H2NC(0)-,
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia
Figure imgf000104_0001
κ9 (Ilia) wherein Rg represents alkyl or aryl, Rι0 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom, or a salt thereof, if applicable.
9. A process for preparing a lactone of formula I,
Figure imgf000104_0002
wherein R2, R3 and R5 are hydrogen and R4 is H2NC(0)- ((+)-discodermolide), wherein a ketone of formula II
Figure imgf000104_0003
wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is hydrogen or H2NC(O)-, is reacted with an aldehyde of formula III
Figure imgf000105_0001
wherein
R5 is a protecting group for a hydroxy group, and
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia
Figure imgf000105_0002
wherein R9 represents alkyl or aryl, R10 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the aldehyde of formula III via the nitrogen atom, to provide a tetraene of formula IV
Figure imgf000106_0001
wherein
R2> R3 and R5 are identical or different protecting groups for a hydroxy group,
R is hydrogen or H2NC(0)-,
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) R8-0-, wherein R8 represents alkyl, or
(c) a substructure of formula Ilia wherein R9 represents alkyl or aryl, Rι0 and R represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom,
wherein the tetraene of formula IV wherein R4 is H2NC(0)- subsequently is the subject of a diastereoselective reduction followed by a lactonization reaction, or of a lactonization reaction followed by a diastereoselective reduction, to provide the lactone of formula I, wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group, or
wherein the tetraene of formula IV wherein R4 is hydrogen, subsequently is the subject of a lactonization reaction followed by a reaction installing the carbamate and a diastereoselective reduction, to provide the lactone of formula I, wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group and ^ is H2NC(0)-,
and wherein finally the protecting groups are split off from the compound of formula I to provide (+)-discodermolide.
10. A process for preparing a lactone of formula IB
Figure imgf000107_0001
wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group and R is H2NC(0)-, wherein in a first step the keto group in a tetraene of formula IV
Figure imgf000107_0002
wherein
R2, R3 and R5 are identical or different protecting groups for a hydroxy group,
R4 is hydrogen or H2NC(0)-, and
R represents
(a) R6-O-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) a substructure of formula Ilia
Figure imgf000108_0001
la)
wherein R9 represents alkyl or aryl, R 0 and Rn represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom, is reduced by a reducing agent capable of transferring an α,β-unsaturated ketone into an α,β-unsaturated alcohol, furnishing a diol of formula LV
Figure imgf000108_0002
wherein
R2, R3 and R5 are identical or different protecting groups for a hydroxy group,
R4 is hydrogen or H2NC(0)-, and
R represents
(a) R6-0-N(R7)- wherein R6 and R7 are independently of each other alkyl or together represent a radical -(CH2)P- wherein p is 3, 4 or 5,
(b) a substructure of formula Ilia
Figure imgf000109_0001
wherein R9 represents alkyl or aryl, Rι0 and R represent independently of each other hydrogen, alkyl or aryl, and which substructure is bound to the rest of the molecule via the nitrogen atom; and thereafter, simultaneously or subsequently, the obtained diol of formula LV is subject of a δ-lactonisation reaction and all protecting groups are removed furnishing (+)- discodermolide.
11. A ketone of formula II
Figure imgf000109_0002
wherein R2 and R3 are identical or different protecting groups for a hydroxy group and R4 is hydrogen or H2NC(0)-.
12. A ketone of formula LIX,
Figure imgf000110_0001
wherein R2, R3 and R5 are identical or different protecting groups for a hydroxy group, and R4 is hydrogen or H2NC(0)-.
13. The δ-valerolacton of the formula VIII
Figure imgf000110_0002
PCT/EP2003/007940 2002-07-22 2003-07-21 Synthesis of discodermolide WO2004009574A1 (en)

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