WO1998048791A1 - Synthese de discodermolide et analogues - Google Patents

Synthese de discodermolide et analogues Download PDF

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Publication number
WO1998048791A1
WO1998048791A1 PCT/US1998/008670 US9808670W WO9848791A1 WO 1998048791 A1 WO1998048791 A1 WO 1998048791A1 US 9808670 W US9808670 W US 9808670W WO 9848791 A1 WO9848791 A1 WO 9848791A1
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Prior art keywords
discodermolide
precursor
synthesis
analogs
mmol
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PCT/US1998/008670
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English (en)
Inventor
David C. Myles
Scott S. Harried
Ge Yang
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The Regents Of The University Of California
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Priority to AU72672/98A priority Critical patent/AU7267298A/en
Publication of WO1998048791A1 publication Critical patent/WO1998048791A1/fr

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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 present invention relates generally to the synthesis of discodermo- lide and analogs thereof. More particularly, the present invention involves the synthesis of three specific precursors of discodermolide which are combined together using the chelation controlled alkylation reaction to form the final discodermolide product.
  • the polyhydroxylated lactone discodermolide is a potent microtubule stabilizing agent showing activity similar to that of taxol.
  • Discodermolide was first isolated from the marine sponge (Discodermia dissoluta) in the early 1990's by scientists at the Harbor Branch Oceanographic Institute. Discoder- molide was initially found to be a promising candidate for immunosuppressive therapy because of its ability to inhibit the proliferation of cultured lymphocytes.
  • Discodermolide is similar to Taxol (Ref. 1) in that it arrests the cell cycle at the G 2 /M boundary (Ref. 2).
  • Ref. 2 Discodermolide is similar to Taxol (Ref. 1) in that it arrests the cell cycle at the G 2 /M boundary (Ref. 2).
  • lOnM a concentration of lOnM
  • extensive microtubule bundling was observed.
  • a factor of 100 higher concentration (1 mM) of taxol was required.
  • discodermolide has shown higher potency than taxol.
  • the toxicity of taxol has been found to be quite high (Ref. 3).
  • the medicinal potential of discodermolide as an immunosuppressive and antimitotic agent have made it the object of substantial synthetic interest.
  • microtubule stabilizing ability of discodermolide has further intensified efforts to produce this drug synthetically.
  • Several partial syntheses of discodermolide have been developed (Refs. 5, 6 and 7).
  • Total syntheses of discodermolide have also been described by Schreiber and coworkers (Ref. 8) and Smith and coworkers (Ref.
  • a method for synthesizing discodermolide.
  • the invention is based on a highly convergent strategy for synthesizing discodermolide which involves disconnecting the carbon backbone of discodermolide at the C-7 to C-8 allylic bond and the C-15 to C-16 allylic bond to provide three subunits which can be synthesized and combined together to form discodermolide.
  • the present invention is particularly well suited for synthesizing relatively large quantities of discodermolide for use as a pharmaceutical or investigative agent.
  • the method may be used to make both the plus and minus enantiomers of discodermolide as well as numerous analogs thereof.
  • first and second precursors are initially combined to form an intermediate compound having the formula:
  • This intermediate compound is then combined with the third precursor to form discodermolide.
  • the highly convergent synthesis of discodermolide in accordance with the present invention takes advantage of a chelation-controlled alkylation reaction to achieve high selection in the key bond coupling reaction.
  • the method and precursors (including analogs) provide an efficient procedure for making discodermolide and structural analogs thereof.
  • FIG. 1 is a diagrammatic representation showing discodermolide and the location at which the carbon backbone is disconnected (C-7 to C-8 allylic bond, C- 15 to C-16 allylic bond and C-21 to C-22 alkyl bond) to thus divide the compound into three key subunit structures which form the basis for synthesis of the complete discodermolide compound.
  • the three key subunits are referenced in FIG. 1 as compounds 2, 3 and 4 or, alternatively, subparts
  • FIG. 2 is a schematic representation of the synthesis of a first precursor (compound 9) which corresponds to subunit B of the discodermolide compound.
  • FIG. 3 is a diagrammatic representation of a synthesis protocol for making an intermediate compound (compound 14) which corresponds to a combination of subparts B and C of discodermolide as represented in FIG. 1. Also, FIG. 3 shows the synthesis of a second precursor (compound 12) which corresponds to subunit C of the discodermolide compound as shown in FIG. 1.
  • FIG. 4 is a diagram of the synthesis of a third precursor for use in making discodermolide which corresponds to subunit A of the total discodermolide compound.
  • FIG. 5 is a diagrammatic representation of the overall synthesis of discodermolide utilizing intermediate compound 14 (combination of precursors 1 and 3) with the third precursor (compound 17).
  • FIG. 6 depicts exemplary analogs of (-) or (+)-Discodermolide which may be made in accordance with the present invention.
  • FIG. 7 depicts additional exemplary analogs of (-) or (+)-Discodermolide which may be made in accordance with the present invention.
  • FIG. 8 depicts exemplary analogs of (-) or (+)-Discodermolide which may be made in accordance with the present invention.
  • (+)-discodermolide when used in this specification is intended to cover both (+) -discodermolide and (-)-discodermolide.
  • the method of the present invention is applicable to synthesizing discodermolide (i.e., both the positive and negative enantiomers) .
  • the present invention may be utilized to synthesize analogs of discodermolide.
  • FIGS. 6-8 set forth exemplary analogs of discodermolide which may be made in accordance with the present invention.
  • (-)-discodermolide is shown as compound 1.
  • the carbon backbone of discodermolide is disconnected to form three target synthetic subunits (2, 3 and 4) which are alternatively referred to as subunits "A,” "B” and "C,” respectively.
  • Discodermolide has a carbon backbone which includes 24 carbon atoms ranging from C-1 to C-24 as best shown in FIG. 1.
  • the synthesis strategy involves making three precursors which correspond to the three subunits which result from disconnecting the carbon backbone at the C-7 to C-8 allylic bond and the C-15 to C-16 allylic bond.
  • the C-22 and C-23 backbone positions for discodermolide are added during the synthesis procedure. Accordingly, the three subunits A, B and C correspond to the C-1 to C-7, C-8 to C-15 and C-16 to C-21 locations on the backbone, respectively.
  • the basic synthetic process can be viewed as either a combination of the three precursors (9, 12 and 17) to form the final product or a combination of the first two precursors (9, 12) to form an intermediate product (14) which is then combined with the third precursor (17) to form discodermolides and analogs thereof.
  • the key coupling reaction (C-15 to C-16) occurs by way of a distereo- selective alkylation reaction between the anion of ethyl ketone 4 and iodine 3.
  • a metal-promoted coupling of a C-8 Z-vinyl iodide with a C-7 aldehyde completes the carbon backbone to form the discodermolide product.
  • the steps in the method of the present invention are set forth in FIGS. 2-5.
  • the synthetic procedure is also disclosed in reference 19.
  • An exemplary synthesis of the first precursor in accordance with the present invention is shown in
  • the first precursor (compound 9) is prepared utilizing dihydro-4- pyrone 7 which is obtained via the diene-aldehyde cyclocondensation reaction of diene 6 and aldehyde 5 (Ref. 10).
  • Reduction of the carbonyl of pyrone 7 is achieved using sodium borohydride in the presence of cerium trichloride to afford the corresponding alcohol as a mixture of diastereomers.
  • Sequential treatment of this material with aqueous p-toluenesulfonic acid followed by lithium borohydride leads to reductive opening of the resultant hemiacetal to afford the desired Z- allylic alcohol 8 in
  • the second precursor is an ethyl ketone having the formula:
  • the second precursor corresponds to subpart "C” and was prepared directly by aldol condensation of the lithium anion of 3-pentanone and i?-3-benzyloxy- 2-methylpropionaldehyde, followed by protection of the resulting alcohol as the methoxymethyl ether (see FIG. 3) (Ref. 13).
  • the methoxymethyl (MOM) protecting group for the alcohol ⁇ to the ketone promotes the desired chelation of the metal counter ion of the enolate. In addition, this protecting group facilitates introduction of the C-19 carbamate function at a late stage in the synthesis.
  • the second precursor can also be made by diastereoselective aldol condensation of aldehyde 11 and oxazolidionone 15 followed by protection of the resulting alcohol as its methoxymethyl ether and homologation to produce compound 12.
  • the diastereo- selectivity of the chelation controlled alkylation shows a remarkable solvent dependence.
  • the diastereo- selectivity is preferably optimized to a level of 6: 1 in the mixed solvent system 45:55 hexanes:THF, favoring the desired diastereomer. Referring to FIG.
  • Third precursor 17 is an aldehyde which corresponds to subpart A and sets the stage for the coupling of the C-7 to C-8 bond to assemble the complete chiral array of discodermolide.
  • the vinyl iodide moiety was prepared from this material by treatment with iodomethlenetriphenyl- phosphorane (Ref. 16). Oxidative cleavage of the C-21 PMB ether using dichlorodicyanoquinone (DDQ) proceeds smoothly to afford alcohol 18. After TPAP oxidation, the Z-diene is prepared following the conditions of Roush (Ref.
  • the above described total synthesis method is highly convergent and can be easily modified using known synthetic procedures to synthesize analogs of discodermolide of the type shown in FIGS. 6-8.
  • Preparative TLC was performed using precoated TLC plates (silica gel F-254, 0.5 mm, Baker). Thin layer chromatography with Chromatron was carried out on silica gel plates of various thicknesses (silica gel 60, PF254, containing gypsum).
  • the oxidation reaction was stirred for 2 hours, during which time the color changed from green to black. At that time, the reaction was judged to be complete by TLC (10% EtOAC in hexanes). The crude mixture was then concentrated in vacuo. The crude residue was purified by column chromatography (4 cm silica gel on a 3 cm diameter column, elute CH2CI2). The eluate was concentrated in vacuo providing clean aldehyde (475 mg) which was dried azeotropically with benzene (1 x 3 mL) in vacuo and then dissolved in THF (10 mL). This solution was immediately used in the following procedure.
  • reaction mixture was then placed in a -78°C bath for 3 minutes before adding the above freshly prepared THF (10 mL) solution of aldehyde via cannula. Care was taken to cool the aldehyde in THF solution by passing it down the side of the reaction flask during the addition.
  • the reaction mixture was stirred for 10 minutes and then quenched by pouring into aqueous NH C1 (1M, 50 mL).
  • the resulting mixture was extracted with EA (3 x 50 mL) and CH2CI2 (1 x 20 mL).
  • the combined organic layers were washed with sat. NaCl (1 x 200 mL) and dried with anhydrous Na 2 S0 .
  • the dried organic layers were filtered through a short plug of silica gel and concentrated in vacuo to provide the crude product (1.75 g).
  • the crude residue was purified by column chromatography (20 cm silica gel on a 3 cm diameter column, 5% EtOAc in hexane) providing clean vinyl iodide as a colorless foamy oil (500 mg, 0.529 mmol) in 80% from the clean oil.
  • the oxidation reaction was allowed to stir for 40 minutes and then judged to be complete (TLC, 10% EtOAc in hexanes) over the 40 minutes of reaction time the color turned from green to black. After 1 hour, the reaction mixture was concentrated in vacuo. The crude residue was purified by column chromatography (5 cm silica gel on a 2 cm diameter column, elute 5% EA in CH2CI2, 100 mL). The eluate was concentrated in vacuo providing clean aldehyde (170 mg), which was immediately used in the following procedure.
  • reaction mixture was purified by column chromatography (20 cm silica gel on a 3 cm diameter column, 5% EA in hexane) by loading reaction mixture directly to the column.
  • the eluate was concentrated in vacuo in a 100 mL round bottom flask providing the expected allylboration adduct, which was immediately used in the following procedure.
  • THF 10 mL
  • the reaction mixture was placed in a 0°C bath and stirred for 10 minutes before adding KH (ca. 100 mg, from 20-25 wt.
  • the reaction was allowed to stir at room temperature for 30 minutes and then directly placed on a short pad of AI2O3 (neutral, activity II) that was pre-wetted with a 1 : 1 benzene:CH 2 Cl 2 solution.
  • the reaction mixture was allowed to soak on the column of AI2O3 for 30 minutes before eluting with 1 :1 benzene:CH2Cl 2 solution (60 mL).
  • Concentration of the eluate provided crude residue (88 mg) which was purified by column chromatography (18 cm silica gel on 2 cm diameter column, 8% EtOAc in hexanes) .
  • Concentration of the eluate in vacuo provided carbamate 19 (62 mg) as a white foamy solid in 78% yield.
  • Discodermolide was synthesized as follows: Aldehyde 17 (19 mg, 0.038 mmol) and the vinyl iodide 19 (36 mg, 0.043 mmol) were added to a flame dried 100 mL pear bottom flask equipped with a magnetic stir bar and a teflon stopcock vacuum adapter was added. The mixture was azeotropically dried with benzene (4 x 0.7 mL) and then placed under high vacuum (2 mm Hg) for 30 minutes. At this time the flask was flushed with argon and evacuated for 2 minutes. This process was repeated several times before ultimately leaving the reaction flask under vacuum while transporting it into an N22 atmosphere dry box.
  • the crude yellowish solid residue from above was dissolved in 10% MeOH in CH 2 CI 2 and transferred to a high density polyethylene vial equipped with a magnetic stir bar.
  • the CH2CI2 was evaporated using a stream of air and then the vial was placed under high vacuum (2 mm Hg) for 5 minutes.
  • reaction vial and solid was azeotropically dried with benzene (1 x 0.1 mL) and then THF (0.3 mL) was added before placing vial in 0°C bath.
  • THF 0.3 mL
  • To the cooled reaction vial was added 0.2 mL of a pre-mixed solution of 1 : 1 THF to HF-Pyr (70% anhydrous HF to 30% anhydrous pyridine). The reaction mixture was allowed to stir at 0°C for 30 minutes before an additional portion

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de fabrication de discodermolide et d'analogues de ce dernier. Ledit procédé fait appel à trois précurseurs qui correspondent à trois sous-parties du discodermolide que l'on forme en scindant le squelette de carbone du discodermolide entre C-7 et C-8 et entre C-15 et C-16. Le couplage des précurseurs s'effectue par une alkylation à chélation contrôlée.
PCT/US1998/008670 1997-04-30 1998-04-30 Synthese de discodermolide et analogues WO1998048791A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002057251A2 (fr) * 2001-01-22 2002-07-25 Novartis Ag Procede de preparation d'intermediaires pour la fabrication de discodermolide et d'analogues de discodermolide
WO2003080567A2 (fr) * 2002-03-27 2003-10-02 Novartis Ag Produits intermediaires destines a la synthese de la discodermolide et de ses analogues, et leurs procedes de preparation
JP2004505963A (ja) * 2000-08-07 2004-02-26 ノバルティス　アクチエンゲゼルシャフト ディスコデルモライドとその類似物の製造方法
WO2004089960A2 (fr) * 2003-04-08 2004-10-21 Isotechnika Inc. Procede pour preparer un analogue de la cyclosporine a

Citations (2)

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Publication number Priority date Publication date Assignee Title
US5010099A (en) * 1989-08-11 1991-04-23 Harbor Branch Oceanographic Institution, Inc. Discodermolide compounds, compositions containing same and method of preparation and use
GB2280677A (en) * 1993-07-30 1995-02-08 Roussel Lab Ltd Total synthesis of discodermolide

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US5010099A (en) * 1989-08-11 1991-04-23 Harbor Branch Oceanographic Institution, Inc. Discodermolide compounds, compositions containing same and method of preparation and use
GB2280677A (en) * 1993-07-30 1995-02-08 Roussel Lab Ltd Total synthesis of discodermolide

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Title
DATABASE STN WPIDS 1 January 1900 (1900-01-01), GILLESPIE R J, GOLEC J M C, JONES S D: "NEW ALDEHYDE CPDS. - USED IN SYNTHESIS OF IMMUNOSUPPESSANT DISCODERMOLIDE VIA NEW INTERMEDIATES", XP002912691, Database accession no. 95-068862 *
EVANS P L, GOLEC J M C, GILLESPIE R J: "THE SYNTHESIS OF A C9-C17 FRAGMENT OF DISCODERMOLIDE", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 34, no. 50, 1 December 1993 (1993-12-01), GB, pages 8163 - 8166, XP002912688, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(00)61480-6 *
GOLEC J M C, GILLESPIE R J: "AN APPROACH TO THE SYNTHESIS OF A C9-C15 FRAGMENT OF DISCODERMOLIDE", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 34, no. 50, 1 December 1993 (1993-12-01), GB, pages 8167/8168, XP002912689, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(00)61481-8 *
HARRIED S S, ET AL.: "TOTAL SYNTHESIS OF (-)-DISCODERMOLIDE: AN APPLICATION OF A CELATION-CONTROLLED ALKYLATION REACTION", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 62, no. 18, 5 September 1997 (1997-09-05), US, pages 6098/6099, XP002912690, ISSN: 0022-3263, DOI: 10.1021/jo9708093 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004505963A (ja) * 2000-08-07 2004-02-26 ノバルティス　アクチエンゲゼルシャフト ディスコデルモライドとその類似物の製造方法
WO2002057251A2 (fr) * 2001-01-22 2002-07-25 Novartis Ag Procede de preparation d'intermediaires pour la fabrication de discodermolide et d'analogues de discodermolide
WO2002057251A3 (fr) * 2001-01-22 2002-10-10 Novartis Ag Procede de preparation d'intermediaires pour la fabrication de discodermolide et d'analogues de discodermolide
US6974875B2 (en) 2001-01-22 2005-12-13 Novartis Ag Process for preparing intermediates for the manufacture of discodermolide and discodermolide analogues
WO2003080567A2 (fr) * 2002-03-27 2003-10-02 Novartis Ag Produits intermediaires destines a la synthese de la discodermolide et de ses analogues, et leurs procedes de preparation
WO2003080567A3 (fr) * 2002-03-27 2004-04-15 Novartis Ag Produits intermediaires destines a la synthese de la discodermolide et de ses analogues, et leurs procedes de preparation
WO2004089960A2 (fr) * 2003-04-08 2004-10-21 Isotechnika Inc. Procede pour preparer un analogue de la cyclosporine a
WO2004089960A3 (fr) * 2003-04-08 2005-01-06 Isotechnika Inc Procede pour preparer un analogue de la cyclosporine a

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