WO2022074068A1 - Disorazoles and their analogues and methods for their production - Google Patents

Disorazoles and their analogues and methods for their production Download PDF

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WO2022074068A1
WO2022074068A1 PCT/EP2021/077602 EP2021077602W WO2022074068A1 WO 2022074068 A1 WO2022074068 A1 WO 2022074068A1 EP 2021077602 W EP2021077602 W EP 2021077602W WO 2022074068 A1 WO2022074068 A1 WO 2022074068A1
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compound
mmol
choch
nmr
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PCT/EP2021/077602
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Dieter Schinzer
Oliver Spiess
Luca LIZZADRO
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Otto-Von-Guericke-Universtiy Magdeburg
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Publication of WO2022074068A1 publication Critical patent/WO2022074068A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/30—Compounds having groups
    • C07C43/315—Compounds having groups containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • Disorazoles and their Analogues and Methods for their Production Technical Field The present invention relates to disorazoles and their analogues and meth- ods for their production. These compounds can be used as medicaments, in particular for the treatment of various tumors.
  • Background Art Disorazoles are potent anti-cancer drugs and are natural substances. It is known that natural substances of the group consisting of the disorazoles are isolated from the bacterium of the strain Sorangium cellulosum. Synthetic methods for the preparation of disorazoles are described, for exam- ple, in WO 2018/237178 A1 or Wipf P. et al., J. Am. Chem. Soc.2004, 126, 47, 15346–15347.
  • the present invention discloses new disorazoles and their analogues and new synthetic methods for the up-scaled production of disora- zoles and their analogues.
  • the disorazoles and their analogues may be produced by using two main substructures, also named as precursors, that can be pro- prised in large scales. These two main substructures are used to produce an open-chained precursor for the final cyclisation of disorazoles and their ana- logues.
  • One preferred embodiment of the present invention is a compound of the formula III wherein: X is O, S, or NR;
  • R is H, or alkyl (c ⁇ 8) ;
  • R 1 is H, alkyl (c ⁇ 8) , or cycloalkyl (c ⁇ 8) ;
  • R 4 is independently H, alkyl (c ⁇ 8) , cycloalkyl (c ⁇ 8) , alkenyl (c ⁇ 8) , alkinyl (c ⁇ 8) , allyl, propargyl, phenyl, or benzyl;
  • Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyrrolyl, thiophenyl, pyridyl, or phenyl;
  • a further preferred embodiment aspect of the present invention are com- pounds of the Formula III, namely
  • Another aspect of the present invention is a method for the production of a compound of formula III
  • X is O, S, or NR
  • R is H, or alkyl (c ⁇ 8) ;
  • R 1 is H, alkyl (c ⁇ 8) , or cycloalkyl (c ⁇ 8) ;
  • R 4 is independently H, alkyl (c ⁇ 8) , cycloalkyl (c ⁇ 8) , alkenyl (c ⁇ 8) , al- kinyl (c ⁇ 8) , allyl, propargyl, phenyl, or benzyl;
  • Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyr- rolyl, thiophenyl, pyridyl, or phenyl;
  • step (a) reacting a compound of formula I wherein R and R 1 is as defined above; with a compound of formula II wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R 2 , R 3 , and R 4 are defined as above; and wherein PG is independently H, or alkyl (c ⁇ 8) ; or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS, (b) reacting the product obtained in step (a) with a compound of formula I, wherein the coupling of the obtained product and compound of for- mula I is performed via the carboxyl ester of compound I and the X group of the obtained product; (c) reacting the product obtained in step (b) with a compound of formula II in the same way as in step (a); (d) cyclizing the product obtained from step (c) obtaining the product of formula III.
  • the main feature of this aspect is that two precursors as disclosed, as com- pounds of formula I and of formula II, are used to produce an open chained precursor of disorazols and their analogues. This open chained precursor is then cyclized and the final products as described as compounds of formula III, namely disorazoles and their analogues, are produced in a high yield and in a great purity.
  • Another aspect of the present invention is a method for the production of a compound of formula III according to claim 1 wherein: X is O, S, or NR;
  • R is H, or alkyl (c ⁇ 8) ;
  • R 1 is H, alkyl (c ⁇ 8) , or cycloalkyl (c ⁇ 8) ;
  • R 4 is independently H, alkyl (c ⁇ 8) , cycloalkyl (c ⁇ 8) , alkenyl (c ⁇ 8) , al- kinyl (c ⁇ 8) , allyl, propargyl, phenyl, or benzyl;
  • Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyrrolyl, thiophenyl, pyridyl, or phenyl;
  • R and R 1 is as defined above; with a compound of formula II wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R 2 , R 3 , and R 4 are defined as above; and wherein PG is independently H, or alkyl (c ⁇ 8) ; or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS, (b) reacting the product of step (a) in two different steps, namely step (b1) and step (b2), wherein in step (b1) the compound obtained in step (a) is modified, in a way that PG from X is removed to obtain a compound wherein X is OH, SH, or NH 2 , and wherein in step (b2) the compound obtained in step (a) is modified, in a way that residue R of the carboxy group is removed and replaced with H; (c) reacting the product obtained in step (
  • An especially preferred embodiment of the present invention is a method for the production of disorazole-C1 of formula 37 comprising the following steps: (a) reacting a compound of formula 30a wherein R is methyl or hydrogen with a compound of formula 18 wherein PG1 is MOM obtaining a compound of formula 31 (b) reacting the compound of formula 31 with a compound of formula 30a, obtaining a compound of formula 32 (c) reacting the compound of formula 32 with a compound of formula 18, obtaining a compound of formula 33
  • step (d) reacting compound of formula 33 into disorazole-C1 of formula 37.
  • step (a) is a coupling re- action combining compounds of formula 18 and of formula 30a, wherein R is methyl.
  • step (b) is an esterifi- cation.
  • step (c) is a cou- pling reaction combining compounds of formula 31 and of formula 30a, wherein R is hydrogen.
  • step (d) comprises the following steps: (d1) saponification of methyl ester from compound of formula 33 to a com- pound of formula 34
  • Another especially preferred embodiment of the present invention is a method for the production of disorazole-C1 of formula 37 comprising the following steps: (a) reacting a compound of formula 30a wherein R and R y are methyl; with a compound of formula 17a wherein PG 1 is methyl and PG 2 is MOM; obtaining a compound of formula 40 wherein R x is PG 1 and R y is methyl as defined above; (b) reacting the compound of formula 40 partially in a step (b1) into a compound of formula 41
  • a further preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula 30a wherein R is methyl or hydrogen.
  • Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula 18 wherein PG1 is MOM.
  • Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula 33 wherein PG1 is MOM.
  • Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula I
  • R and R 1 is as defined above.
  • Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula II wherein X is O, S, or NR as defined above and wherein O, S, or NR com- prise further a protective group PG; wherein R 2 , R 3 , and R 4 are defined as above; and wherein PG is independently H, or alkyl (c ⁇ 8) ; or a protective group selected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS.
  • a great advantage of the present invention is that only two precursors are needed to synthesize disorazoles and their analogues, namely compounds of formula I, formula II, formula 18, formula 30a, formula 29, or formula 30.
  • Another great advantage of the present invention is to combine also com- pound of formula 17a with compound of formula 30a with different protective groups or substituents as described below in scheme 6.
  • Another great advantage is that the precursors used can be selected accord- ing to their stereospecific properties.
  • the compounds of formula I comprises one asymmetric carbon atom.
  • the compounds of formula II comprise up to three asymmetric carbon atoms.
  • the final product of formula III con- tains up to eight asymmetric centres and all possible combinations of the dia- stereomers can be produced easily. This option is one of the greatest ad- vantages of the present invention.
  • One preferred embodiment of the present invention is the production of diso- razole C1 .
  • a high yield in the production of the final product is also a great advantage.
  • a further object of the present invention is a pharmaceutical preparation for the treatment of cancer diseases, comprising at least one compound accord- ing to the invention and other acceptable excipients, adjuvants and /or addi- tives.
  • L-serin methyl ester is reacted with compound of formula 25 to form the respective amide.
  • a cyclisation of the amide according to formula 26 is performed and this results to an oxazoline deriva- tive.
  • the oxazoline is oxidized in order to obtain the oxazole derivative according to formula 28.
  • the protective group in the compound of formula 28 is then removed and compound of formula 29 is obtained.
  • This compound will be used for the final reaction as one of the starting materials indicated as compound of Formula 30a.
  • the compound of formula 30a is a combination of compounds of formula 29 and 30, which differ from each other in the ester function of the carboxyl group.
  • compound of formula 29 is saponificated to remove the methyl group from the ester group in the compound of formula 29.
  • final product of formula 30 is obtained.
  • compounds of formula 29 and formula 30 will be used in combination with the compound of formula 18 for the final reaction steps to obtain the final product disorazole of formula 37.
  • the total synthesis of disorazole of the formula 37 is performed in the follow- ing steps.
  • the compounds of formula 18 and formula 29 are coupled. Especially pre- ferred is the use of a Sonogashira reaction.
  • Compound of formula 31 is pro- Jerusalem and an esterification with compound of formula 30 is performed in the next step, wherein compound of formula 32 is obtained.
  • compound of formula 32 and compound of formula 18 are coupled, especially preferred also with a Sonogashira reaction.
  • the reaction produces the open- chained compound of formula 33.
  • the next steps of the reactions according to Scheme 5 perform the cyclisa- tion of compound of formula 33, forming the final product, disorazole of for- mula 37.
  • reaction Scheme 6 the carboxyl group is methylated. All reactive groups are protected so that the step a), as indicated in Scheme 6, is performed as a Sonogashira reaction, as described in Scheme 5.
  • step b) the product 40 is now reacted in two different steps in or- der to obtain the products 41 and 42.
  • the products 41 and 42 differ from each other only in one reactive group.
  • step b) as indicated in Scheme 6, which is a simple demethylation step, Rx, the methyl group is removed and changed into hydrogen, so that a free hydroxyl group is present in the com- pound of formula 41.
  • step c) compound of for- mula 40 is demethylated in a simple saponification step and results in a free carboxylic group as indicated in the compound of formula 42.
  • step d) as indicated in Scheme 6, a Yamaguchi reaction is performed as a lactoniza- tion of compounds of formula 41 and 42 into compound of formula 43.
  • step e) and f) as indicated in Scheme 6, the protective groups are re- moved as already shown in steps b) and c) , as indicated in Scheme 6.
  • the final cyclization reaction to obtain the disorazole according to the present in- vention is performed, for example, in the same way as shown in Scheme 5 , as indicated above.
  • MOM meth- oxymethyl
  • MEM ((2-methoxyethoxy)phenyl)
  • THP tetrahydropyranyl
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TIPS triisopropylsilyl
  • TBS tert-butyldime- thylsilyl
  • TBDPS tert-butyldiphenylsilyl
  • OAc O-Acyl
  • Example 1 (S)-(+)-Mandelic acid methyl ester (1) To a solution of (S)-(+)-Mandelic acid (57.13 g, 376 mmol, 1 eq) in MeOH (300 mL), concentrated sulfuric acid (600 ⁇ L, 11.3 mmol, 0.03 eq) was added and the mixture was refluxed for 4 h. The reaction was quenched with K 2 CO 3 (1.04 g, 7.52 mmol, 0.02 eq) in 1.2 mL of water and the MeOH was evapo- rated in vacuo.
  • Example 4 Ethyl 3-hydroxy-2,2-dimethylpentanoate (4) n-BuLi (133 mL, 332.38 mmol, 1.1 eq, 2.5 M solution in hexane) was added dropwise at -78°C to a solution of diisopropylamine (46.5 mL, 332.37 mmol, 1.1 eq) in THF (300 mL). This LDA solution was stirred for 30 min at 0°C and then cooled to -78°C.
  • ester 5 (29.85 g, 191.25 mmol, 68%) as a colorless liquid.
  • Example 8 (1S)-2-Hydoxy-1,2,2-triphenylethl (3S,5E)-3hydoxy-4,4-dimethyl-5-hep- tenoate (8) n-BuLi (22.5 mL, 56.32 mmol, 2.2 eq, 2.5 M solution in hexane) was added dropwise at -78°C to a solution of diisopropylamine (7.9 mL, 56.32 mmol, 2.2 eq) in THF (80 mL).
  • Example 9 (3S,5E)-4,4-dimethyl-5-heptene-1,3-diol (9) 8 LiAlH 4 (5.2 g, 137.97 mmol, 7.0 eq) was added portionwise to a refluxing so- lution of ⁇ -hydroxy ester 13 (8.75 g, 19.71 mmol, 1 eq) in Et 2 O (210 mL), dur- ing a period of 2 h. Reflux was continued for 30 min. After cooling to 0°C, the reaction was quenched by dropwise addition of water (10 mL).
  • Example 12 (4S,6S)-5,5-dimethyl-6,8-bis((triethylsilyl)oxy)oct-1-en-4-ol (12)
  • Leighton reagent (4.74 g, 8.58 mmol, 1.2 eq) in CH 2 Cl 2 (20 mL) was added to a solution of aldehyde 11 (2.67 g, 7.15 mmol, 1 eq) in CH 2 Cl 2 (50 mL).
  • Sc(OTf) 3 (175 mg, 0.375 mmol, 0.05 eq) was added and the mixture was stirred for 24 h at room temperature.
  • TBAF trihydrate (2.26 g, 7.15 mmol, 1 eq) was added and the mixture was stirred for 30 min at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (pentane/Et 2 O 50:1, then pentane/EtOAc/NEt 3 1:1:0.1) to furnish the allylic alcohol (2.36 g, 5.65 mmol, 80%) as a colorless liquid and the recovered diamine (3.64 g, 8.08 mmol, 87 %) as a yellow paste.
  • Example 13 (5S,7S)-5-allyl-11,11-diethyl-6,6-dimethyl-7-((triethylsilyl)oxy)-2,4,10-tri- oxa-11-silatridecane (13)
  • MOMCl 1.3 mL, 17 mmol, 3 eq
  • DIPEA 3 mL, 17 mmol, 3 eq
  • DMAP 207 mg, 1.7 mmol, 0.3 eq
  • Example 14 (3S,5S,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl)oxy)non-7- en-1-ol
  • a solution of protected triol 13 (2.3 g, 5 mmol, 1 eq) and Grubbs II (212 mg, 0.250 mmol, 0.05 eq) in MeOH was stirred overnight at 60°C.
  • the mixture was then concentrated in vacuo and the residue was filtered on a pad of sil- ica gel (Pen/Et 2 O 1:1).
  • the filtrate was concentrated in vacuo affording a mix- ture of 15 (80%) and 14 (15%) as a colorless liquid, which was used in the next step without further purification.
  • Example 15 (3S,5S,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl)oxy)oct-6- enal (16) DMSO (0.780 mL, 11 mmol, 2 eq) in CH 2 Cl 2 (5 mL) was added dropwise to a solution of oxalyl chloride (0.644 mL, 7.5 mmol, 1.2 eq) in CH 2 Cl 2 (20 mL) at - 78°C. The mixture was stirred for 10 min at -78°C and then the crude 14 + 15 dissolved in CH 2 Cl 2 (5 mL) was added dropwise.
  • Example 16 (5S,7S)-9,9-diethyl-7-((Z)-3-iodoallyl)-6,6-dimethyl-5-((E)-prop-1-en-1-yl)- 2,4,8-trioxa-9-silaundecane (17) NaHMDS (1 M in THF, 4.2 mL, 4.2 mmol, 1.5 eq) was added dropwise at 0°C to a solution of IMePPh3I (2.22 g, 4.2 mmol, 1.5 eq) in THF (30 mL). The red solution was stirred for 10 min at room temperature and then cooled to -78°C.
  • Example 17 (1Z,4S,6S,7E)-1-iodo-6-(methoxymethoxy)-5,5-dimethylnona-1,7-dien-4- ol (18) CSA (93 mg, 0.4 mmol, 0.2 eq) was added at 0°C to a solution of Z Iodide 17 (940 mg, 2 mmol, 1 eq) in CH 2 Cl 2 (50 mL) and MeOH (50 mL). The mixture was stirred for 1 h at 0°C without N2. Saturated NaHCO 3 solution (100 mL) was added and the layers were separated.
  • reaction mixture was then filtered through a pad of Celite and the filtrate was washed with saturated aqueous solution of NaHSO 4 to remove Proton Sponge.
  • the aqueous phase was extracted with CH 2 Cl 2 and the organic extracts were dried over Na 2 SO 4 , filtered and concen- trated in vacuo.
  • the residue was purified by silica gel chromatography (Pen/Et 2 O 20:1, then 2:1) to give 21 (3.91 g, 21.03 mmol, 77%) as a color- less liquid and unreacted alcohol (517 mg, 3.00 mmol, 11%).
  • Example 20 tert-butyl (R)-3-methoxy-4-oxobutanoate (22) A stream of O 3 in O 2 was bubbled through a solution of (R)-21 (3.23 g, 17.37 mmol, 1 eq) in CH 2 Cl 2 (75 mL) and MeOH (15 mL) at -78°C until the blue color of the solution persisted. Then O 2 was bubbled for 10 min and PPh3 (5.47 g, 20.84 mmol, 1.2 eq) was added. The mixture was warmed to room temperature and stirred for 2 h.
  • Example 21 tert-Butyl (R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynoate (24) nBuLi 2.5 M in hexane (8 mL, 20.05 mmol, 1.3 eq) was added dropwise to a suspension of Phosphonium Bromide 23 (9.96 g, 18.5 mmol, 1.2 eq) in THF (100 mL) at -78°C. The red solution was stirred at 0°C for 30 min and then aldehyde 22 (2.9 g, 15.42 mmol, 1 eq) in THF (20 mL) was added dropwise.
  • Phosphonium Bromide 23 9.96 g, 18.5 mmol, 1.2 eq
  • THF 100 mL
  • aldehyde 22 2.9 g, 15.42 mmol, 1 eq
  • Car- bossilic acid 25 was obtained (2.68 g, 8.65 mmol, 99%) as a slightly yellow liquid.
  • Example 23 methyl ((R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynoyl)-L-seri- nate (26) DIPEA (3.5 mL, 20.1 mmol, 2.3 eq) and TFFH (2.54 g, 9.61 mmol, 1.1 eq) were added to a solution of carboxylic acid 26 (2.7 g, 8.74 mmol, 1 eq) in THF (30 mL) and the mixture was stirred for 2 h at room temperature.
  • Example 24 Methyl 2-((R,E)-2-methoxy-6-(triisopropylsilyl)hex-3-en-5-yn-1-yl)-4,5- dihydrooxazole-4-carboxylate (27) DAST (1.13 mL, 8.56 mmol, 1.1 eq) was added dropwise to a solution of serinate 26 (3.2 g, 7.78 mmol, 1 eq) in CH 2 Cl 2 (60 mL) at -78°C and the mix- ture was stirred for 2 h at -78°C. K2CO 3 (2.15 g, 15.56 mmol, 2 eq) was added and the mixture was warmed to room temperature and stirred for 1 h.
  • Example 25 Methyl (R,E)-2-(2-methoxy-6-(triisopropylsilyl)hex-3-en-5-yn-1- yl)oxazole-4-carboxylate (28)
  • the crude material 27 was dissolved in CH 2 Cl 2 (60 mL), cooled to 0°C and protected from light with aluminium foil.
  • DBU (2.24 mL, 15.56 mmol, 2 eq) and BrCCl 3 (1.53 mL, 15.56 mmol, 2 eq) were sequentially added dropwise, then the bath was removed and the mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NH 4 Cl solution (100 mL) and the layers were separated.
  • Example 26 Methyl (R,E)-2-(2-methoxyhex-3-en-5-yn-1-yl)oxazole-4-carboxylate (29) TBAF (1 M in THF, 4.6 mL, 4.6 mmol, 1.2 eq) was added dropwise at 0°C to a solution of TIPS oxazole 28 (1.5 g, 3.83 mmol, 1 eq) in THF (10 mL). The mixture was stirred for 1 h at room temperature and then quenched with wa- ter. The aqueous phase was extracted with Et 2 O and the organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Example 27 (R,E)-2-(2-methoxyhex-3-en-5-yn-1-yl)oxazole-4-carboxylic acid (30) LiOH (1 M in H 2 O, 3.9 mL, 3.9 mmol, 2.5 eq) was added to a solution of the oxazole 29 (367 mg, 1.56 mmol, 1 eq) in THF (1 mL) at room temperature. The mixture was stirred for 2 h and then quenched with 1 M HCl. The aque- ous phase was extracted with Et 2 O and the organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford the acid 30 (326 mg, 1.54 mmol, 99%) as a yellow solid.
  • Example 28 Methyl 2-((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2-methoxy-12-(methox- ymethoxy)-11,11-dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4- carboxylate
  • the vinyl iodide 18 300 mg, 0.847 mmol, 1 eq
  • Example 29 (2E,4S,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)oxazol-2-yl)- 4-(methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn-6-yl 2- ((R,E)-2-methoxyhex-3-en-5-yn-1-yl)oxazole-4-carboxylate (32)
  • the monomer 31 (320 mg, 0.694 mmol, 1 eq) and the acid 30 (291 mg, 1.32 mmol, 1.5 eq) and DMAP (85 mg, 0.694 mmol, 1 eq) were dissolved in CH 2 Cl 2 (10 mL) and cooled to 0°C.
  • Example 32 (16,16’)-Bis(methoxymethyl)-(9,10,9’,10’)-tetradehydridodisorazole C1 (35)
  • the crude seco-acid 34 (28 mg, 0.0319 mmol, 1 eq) was dissolved in THF (2.5 mL) and NEt 3 (89 ⁇ L, 0.638 mmol, 20 eq) and TCBC (50 ⁇ L, 0.319 mmol, 10 eq) were added at room temperature.
  • Example 33 (16,16’)-Bis(methoxymethyl)-disorazole C1 (36) Nitrogen is bubbled for 15 min through a suspension of Zinc (3 g, 45.88 mmol) in H 2 O (18 mL) and then Cu(OAc) 2 ⁇ H 2 O (300 mg, 1.50 mmol) was added at room temperature and after 15 min AgNO 3 (300 mg, 1.77 mmol) was added (exothermic reaction). The mixture was stirred for 30 min at room temperature, filtered by suction and washed with H 2 O (30 mL), MeOH (20 mL), acetone (20 mL) and Et 2 O (20 mL).
  • Example 35 Methyl 2-((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)- 11,11-dimethyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)ox- azole-4-carboxylate (40)
  • the vinyl iodide 17 (397 mg, 0.847 mmol, 1 eq) was dissolved in degassed CH 3 CN (5 mL) and CuI (39 mg, 0.254 mmol, 0.3 eq) and PdCl 2 (PPh 3 ) 2 (60 mg, 0.0847 mmol, 0.1 eq) were added.
  • Example 40 Disorazole C1 (37) The intermediate product from Example 39 can be reacted according to the sequence of Example 33 followed by Example 34, as indicated above.
  • Examples 41 to 52 disclose the synthesis of (4R)-Disorazole C1 (37r)
  • a solution of (S,S)-Leighton reagent (4.74 g, 8.58 mmol, 1.2 eq) in CH 2 Cl 2 (20 mL) was added to a solution of aldehyde 11 (2.67 g, 7.15 mmol, 1 eq) in CH 2 Cl 2 (50 mL).
  • Example 42 (5R,7S)-5-allyl-11,11-diethyl-6,6-dimethyl-7-((triethylsilyl)oxy)-2,4,10- trioxa-11- silatridecane (13r) MOMCl (1.3 mL, 17 mmol, 3 eq) was added dropwise at 0°C to a solution of allylic alcohol 12r (2.36 g, 5.67 mmol, 1 eq), DIPEA (3 mL, 17 mmol, 3 eq) and DMAP (207 mg, 1.7 mmol, 0.3 eq) in CH 2 Cl 2 (60 mL). The mixture was stirred overnight at 45°C.
  • Example 43 (3S,5R,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl)oxy)non-7- en-1-ol (14r)
  • a solution of protected triol 13r (2.3 g, 5 mmol, 1 eq) and Grubbs II (212 mg, 0.250 mmol, 0.05 eq) in MeOH was stirred for 20 h at 60°C. The mixture was then concentrated in vacuo and the residue was filtered on a pad of silica gel (Pen/Et 2 O 1:1).
  • Example 46 Methyl 2-((2R,3E,7Z,10S,12R,13E)-2-methoxy-12-(methoxymethoxy)- 11,11-dimethyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1- yl)oxazole-4-carboxylate (40r)
  • the vinyl iodide 17r (397 mg, 0.847 mmol, 1 eq) was dissolved in degassed CH 3 CN (5 mL) and CuI (39 mg, 0.254 mmol, 0.3 eq) and PdCl 2 (PPh 3 ) 2 (60 mg, 0.0847 mmol, 0.1 eq) were added.
  • CSA 13 mg, 0.0521 mmol, 0.2 eq was added at 0°C to a solution of TES protected monomer 40r (150 mg, 0.261 mmol, 1 eq) in CH 2 Cl 2 (7 mL) and MeOH (7 mL). The mixture was stirred for 1 h at 0°C under normal atmos- phere. Saturated aqueous NaHCO 3 solution (15 mL) was added and the lay- ers were separated. The aqueous phase was extracted with CH 2 Cl 2 (3x10 mL) and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the crude acid 42r (91 mg, 0.162 mmol, 1.5 eq) was dissolved in THF (5 mL) treated at room temperature with NEt3 (90 ⁇ L, 0.648 mmol, 6 eq) and 2,4,6- trichlorobenzoyl chloride (68 ⁇ L,0.432 mmol, 4 eq).
  • the turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added dropwise to a solution of alcohol 31r (50 mg, 0.108 mmol, 1 eq) and DMAP (79 mg, 0.648 mmol, 6 eq) in toluene (5 mL).
  • Example 53 (R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynamide (21t)
  • Carboxylic acid 25 (2.3 g, 7.41 mmol, 1 eq) was dissolved in THF (40 mL), cooled to 0°C and ethyl chloroformate (0.917 mL, 9.63 mmol, 1.3 eq) was ad- ded dropwise, followed by NEt 3 (1.44 mL, 10.37 mmol, 1.4 eq). The mixture was stirred for 30 min at 0°C and then 25% aqueous NH 4 OH solution (3 mL) was added.
  • Example 55 Methyl (R,E)-2-(2-methoxy-6-(triisopropylsilyl)hex-3-en-5-yn-1-yl)thia- zole-4-carboxylate (52t) NaHCO 3 (2.3 g, 27.05 mmol, 5 eq) was added portionwise to a solution of 51t (1.76 g, 5.41 mmol, 1 eq) in THF (45 mL) at 0°C, followed by a dropwise addition of methyl bromopyruvate (1.73 mL, 16.23 mmol, 3 eq).
  • Example 56 Methyl (R,E)-2-(2-methoxyhex-3-en-5-yn-1-yl)thiazole-4-carboxylate (53t) TIPS thiazole 52t (1.4 g, 3.44 mmol, 1 eq) was carefully dried under high vac- uum, dissoved in THF (35 mL) and cooled to 0°C. TBAF (1 M in THF, 3.78 mL, 3.78 mmol, 1.1 eq) was added dropwise and the mixture was stirred for 30 min at room temperature and then quenched with water (30 mL).
  • Example 57 Methyl 2-((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)- 11,11-dimethyl-10-((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)thi- azole-4-carboxylate (54t)
  • the vinyl iodide 17 (595 mg, 1.27 mmol, 1 eq) was dissolved in degassed CH 3 CN (12 mL) and CuI (57 mg, 0.381 mmol, 0.3 eq) and PdCl 2 (PPh3)2 (89 mg, 0.127 mmol, 0.1 eq) were added.
  • the mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -15°C (ice/acetone bath).
  • NEt 3 (1.06 mL, 7.62 mmol, 6 eq) was added, followed by a slow addition of the enyne 53t (383 mg, 1.52 mmol, 1.2 eq) in degassed CH 3 CN (3 mL).
  • Example 58 Methyl 2-((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2-methoxy-12-(methoxy- methoxy)-11,11-dimethylpentadeca-3,7,13-trien-5-yn-1-yl)thiazole-4-car- boxylate (55t) CSA (18 mg, 0.0744 mmol, 0.2 eq) was added at 0°C to a solution of TES protected monomer 54t (220 mg, 0.372 mmol, 1 eq) in CH 2 Cl 2 (9 mL) and MeOH (9 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere.
  • Example 61 Bis(thiazolyl)-(16,16’)-bis(methoxymethyl)-(9,10,9’,10’)-tetradehydrido- disorazole C1 (58t) CSA (8 mg, 0.0324 mmol, 0.2 eq) was added at 0°C to a solution TES pro- tected dimer 57t (168 mg, 0.162 mmol, 1 eq) in CH 2 Cl 2 (8 mL) and MeOH (8 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Satu- rated NaHCO 3 solution (20 mL) was added and the layers were separated.
  • the crude seco-acid was dissolved in THF (10 mL) and treated at room tem- perature with NEt 3 (506 ⁇ L, 3.24 mmol, 20 eq) and 2,4,6-trichlorobenzoyl chlo- ride (225 ⁇ L, 1.62 mmol, 10 eq).
  • the turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added dropwise to a so- lution of DMAP (791 mg, 6.48 mmol, 40 eq) in toluene (80 mL).
  • Example 62 Bis(thiazolyl)-(16,16’)-bis(methoxymethyl)-disorazole C1 (59t) Nitrogen was bubbled for 15 min through a suspension of Zinc (6 g, 91.77 mmol) in H 2 O (30 mL) and then Cu(OAc)2 ⁇ H 2 O (600 mg, 3.00 mmol) was added at room temperature and after 15 min AgNO 3 (600 mg, 3.53 mmol) was added (exothermic reaction). The mixture was stirred for 30 min at room temperature, filtered by suction and washed with H 2 O (40 mL), MeOH (30 mL), acetone (30 mL) and Et 2 O (30 mL).
  • Example 63 Bis(thiazolyl)-Disorazole C1 (60t) MOM protected 59t (12 mg, 13.4 ⁇ mol) was dissolved in CH 3 CN (1.5 mL) and cooled to 0°C. 2 drops of HBr (48% in H 2 O) were slowly added and then the mixture was stirred for 1 h at 0°C. The mixture was diluted with EtOAc (4 mL) and washed with saturated aqueous NaHCO 3 solution (3 mL). The aqueous phase was extracted with EtOAc (3x5 mL) and the organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo.

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Abstract

The present invention describes disorazoles and their analogues as described in formula III wherein the variables are defined in the description, or pharmaceutically acceptable salts thereof. Described is also a novel synthetic pathway for the production of disorazoles and their analogues, using two precursors twice in coupling reactions and a final cyclisation for a compound of formula III. The compounds of the present invention are useful as anti-cancer drugs.

Description

Disorazoles and their Analogues and Methods for their Production Technical Field The present invention relates to disorazoles and their analogues and meth- ods for their production. These compounds can be used as medicaments, in particular for the treatment of various tumors. Background Art Disorazoles are potent anti-cancer drugs and are natural substances. It is known that natural substances of the group consisting of the disorazoles are isolated from the bacterium of the strain Sorangium cellulosum. Synthetic methods for the preparation of disorazoles are described, for exam- ple, in WO 2018/237178 A1 or Wipf P. et al., J. Am. Chem. Soc.2004, 126, 47, 15346–15347. Therefore, it is an object of the present invention to provide a production method resulting in a high yield of disorazoles and their analogues, especially disorazole C1. Summary of Invention In some aspects, the present invention discloses new disorazoles and their analogues and new synthetic methods for the up-scaled production of disora- zoles and their analogues. One aspect is, that the disorazoles and their analogues may be produced by using two main substructures, also named as precursors, that can be pro- duced in large scales. These two main substructures are used to produce an open-chained precursor for the final cyclisation of disorazoles and their ana- logues. One preferred embodiment of the present invention is a compound of the formula III
Figure imgf000003_0001
wherein: X is O, S, or NR;
R is H, or alkyl(c≤8);
R1 is H, alkyl(c≤8), or cycloalkyl(c≤8);
R2 and R3 are each independently H, alkyl(c≤8), (CH2)n (n = 1 -5);
R4 is independently H, alkyl(c≤8), cycloalkyl(c≤8), alkenyl(c≤8), alkinyl(c≤8), allyl, propargyl, phenyl, or benzyl;
Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyrrolyl, thiophenyl, pyridyl, or phenyl;
* indicate the stereoisomeric centers of the compound; as well as the individual stereoisomers of this compound and/or a pharmaceutically acceptable salt thereof.
A further preferred embodiment aspect of the present invention are com- pounds of the Formula III, namely
(4R)-Disorazole C1 of formula 31 r
Figure imgf000004_0001
Bis(thiazolyl)-Disorazole C1 of formula 60t
Figure imgf000004_0002
Another aspect of the present invention is a method for the production of a compound of formula III
Figure imgf000005_0002
wherein:
X is O, S, or NR;
R is H, or alkyl(c≤8);
R1 is H, alkyl(c≤8), or cycloalkyl(c≤8);
R2 and R3 are each independently H, alkyl(c≤8), (CH2)n (n = 1-5);
R4 is independently H, alkyl(c≤8), cycloalkyl(c≤8), alkenyl(c≤8), al- kinyl(c≤8), allyl, propargyl, phenyl, or benzyl;
Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyr- rolyl, thiophenyl, pyridyl, or phenyl;
* indicate the stereoisomeric centers of the compound; comprising the following steps:
(a) reacting a compound of formula I
Figure imgf000005_0001
wherein R and R1 is as defined above; with a compound of formula II
Figure imgf000006_0001
wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R2, R3, and R4 are defined as above; and wherein PG is independently H, or alkyl(c≤8); or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS, (b) reacting the product obtained in step (a) with a compound of formula I, wherein the coupling of the obtained product and compound of for- mula I is performed via the carboxyl ester of compound I and the X group of the obtained product; (c) reacting the product obtained in step (b) with a compound of formula II in the same way as in step (a); (d) cyclizing the product obtained from step (c) obtaining the product of formula III. The main feature of this aspect is that two precursors as disclosed, as com- pounds of formula I and of formula II, are used to produce an open chained precursor of disorazols and their analogues. This open chained precursor is then cyclized and the final products as described as compounds of formula III, namely disorazoles and their analogues, are produced in a high yield and in a great purity. Another aspect of the present invention is a method for the production of a compound of formula III according to claim 1
Figure imgf000007_0001
wherein: X is O, S, or NR;
R is H, or alkyl(c≤8);
R1 is H, alkyl(c≤8), or cycloalkyl(c≤8);
R2 and R3 are each independently H, alkyl(c≤8), (CH2)n (n = 1 -5);
R4 is independently H, alkyl(c≤8), cycloalkyl(c≤8), alkenyl(c≤8), al- kinyl(c≤8), allyl, propargyl, phenyl, or benzyl;
Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyrrolyl, thiophenyl, pyridyl, or phenyl;
* indicate the stereoisomeric centers of the compound; comprising the following steps:
(a) reacting a compound of formula I
Figure imgf000008_0001
wherein R and R1 is as defined above; with a compound of formula II
Figure imgf000008_0002
wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R2, R3, and R4 are defined as above; and wherein PG is independently H, or alkyl(c≤8); or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS, (b) reacting the product of step (a) in two different steps, namely step (b1) and step (b2), wherein in step (b1) the compound obtained in step (a) is modified, in a way that PG from X is removed to obtain a compound wherein X is OH, SH, or NH2, and wherein in step (b2) the compound obtained in step (a) is modified, in a way that residue R of the carboxy group is removed and replaced with H; (c) reacting the product obtained in step (b1) with the product obtained in step (b2); (d) cyclizing the product obtained from step (c) obtaining the product of formula III. An especially preferred embodiment of the present invention is a method for the production of disorazole-C1 of formula 37
Figure imgf000009_0001
comprising the following steps: (a) reacting a compound of formula 30a
Figure imgf000009_0002
wherein R is methyl or hydrogen with a compound of formula 18
Figure imgf000009_0003
wherein PG1 is MOM obtaining a compound of formula 31
Figure imgf000010_0001
(b) reacting the compound of formula 31 with a compound of formula 30a, obtaining a compound of formula 32
Figure imgf000010_0002
(c) reacting the compound of formula 32 with a compound of formula 18, obtaining a compound of formula 33
Figure imgf000011_0001
(d) reacting compound of formula 33 into disorazole-C1 of formula 37. Especially preferred herein is the method, wherein step (a) is a coupling re- action combining compounds of formula 18 and of formula 30a, wherein R is methyl. Especially preferred herein is also the method, wherein step (b) is an esterifi- cation. Further especially preferred herein is the method, wherein step (c) is a cou- pling reaction combining compounds of formula 31 and of formula 30a, wherein R is hydrogen. Preferred herein is also the method, wherein step (d) comprises the following steps: (d1) saponification of methyl ester from compound of formula 33 to a com- pound of formula 34
Figure imgf000012_0001
(d2) macrolactonisation of open-chained compound 34 into compound of for- mula 35
Figure imgf000012_0002
(d3) reduction of the triple bonds of compound of formula 35 forming com- pound of formula 36
Figure imgf000013_0001
(d4) removing the protection groups to obtain compound of formula 37. Another especially preferred embodiment of the present invention is a method for the production of disorazole-C1 of formula 37
Figure imgf000013_0002
comprising the following steps: (a) reacting a compound of formula 30a
Figure imgf000014_0001
wherein R and Ry are methyl; with a compound of formula 17a
Figure imgf000014_0002
wherein PG1 is methyl and PG2 is MOM; obtaining a compound of formula 40
Figure imgf000014_0003
wherein Rx is PG1 and Ry is methyl as defined above; (b) reacting the compound of formula 40 partially in a step (b1) into a compound of formula 41
Figure imgf000015_0001
and partially in a step (b2) into a compound of formula 42
Figure imgf000015_0002
(c) reacting the compound of formula 41 with the compound of formula 42, obtaining a compound of formula 43
Figure imgf000015_0003
(d) removing Rx and Ry and replacing with hydrogen, obtaining a com- pound of formula 44
Figure imgf000016_0001
(e) reacting compound of formula 44 into disorazole-C1 of formula 37 as described above, wherein the starting compound is the compound of formula 44 instead of formula 34. A great advantage of this embodiment is that the yield of the reaction and the purity of the products is much higher. The reason is, that the complete reac- tion is more effective, as the coupled compounds 41 and 42 from precursors 17a and 30a differ in the protective groups. The different compounds 41 and 42 can easily be produced from the same precursors 17a and 30a. The fur- ther details are described below in reaction scheme 6. A further preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula 30a
Figure imgf000016_0002
wherein R is methyl or hydrogen. Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula 18
Figure imgf000017_0001
wherein PG1 is MOM. Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula 33
Figure imgf000017_0002
wherein PG1 is MOM. Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula I
Figure imgf000018_0001
wherein R and R1 is as defined above. Another preferred embodiment of the present invention is an intermediate product, for the production according to the present invention, according to formula II
Figure imgf000018_0002
wherein X is O, S, or NR as defined above and wherein O, S, or NR com- prise further a protective group PG; wherein R2, R3, and R4 are defined as above; and wherein PG is independently H, or alkyl(c≤8); or a protective group selected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS. A great advantage of the present invention is that only two precursors are needed to synthesize disorazoles and their analogues, namely compounds of formula I, formula II, formula 18, formula 30a, formula 29, or formula 30. Another great advantage of the present invention is to combine also com- pound of formula 17a with compound of formula 30a with different protective groups or substituents as described below in scheme 6. Another great advantage is that the precursors used can be selected accord- ing to their stereospecific properties. The compounds of formula I comprises one asymmetric carbon atom.
Figure imgf000019_0001
The compounds of formula II comprise up to three asymmetric carbon atoms.
Figure imgf000019_0002
For the person skilled in the art it is there therefore clear that the asymmetric centres in the final disorazoles can be produced easily by selecting the re- spective precursors as indicated above. The final product of formula III con- tains up to eight asymmetric centres and all possible combinations of the dia- stereomers can be produced easily. This option is one of the greatest ad- vantages of the present invention.
Figure imgf000020_0001
One preferred embodiment of the present invention is the production of diso- razole C1 . A high yield in the production of the final product is also a great advantage.
A further object of the present invention is a pharmaceutical preparation for the treatment of cancer diseases, comprising at least one compound accord- ing to the invention and other acceptable excipients, adjuvants and /or addi- tives.
It is known in the state of the art how to produce pharmaceutical prepara- tions, especially when using disorazols as known in the art.
Description of Embodiments The process for the production of disorazole and their analogues according to the invention will now be described in great detail. The following reaction schemes describe the synthesis of disorazoles and their analogues in gen- eral. One preferred embodiment of the synthesis in described in the exam- ples as given below in greater details. These examples are one preferred synthetic pathway for the production of disorazole C1. One compound for the production of disorazole is (S)-HYTRA ((S)-(-)-2-Hy- droxy-1,2,2-triphenylethylacetate), which is a protective group. The synthetic pathway is described in Scheme 1.
Figure imgf000021_0001
In order to produce the important precursor of formula 18, which is described as lateral chain, a first fragment is synthesized as described in Scheme 2.
Figure imgf000022_0001
Using (S)-HYTRA of formula 3 and the aldehyde of formula 7 (as shown in Scheme 2) the synthesis of precursor of formula 18 is described in Scheme 3. Aldehyde 7 is reacted with compound of formula 3, then reacted with lith- ium aluminium hydride. An addition of protection groups, preferably with TES, is performed in the next step. The next step is an by ozonolysis, followed by a chiral allylation (preferably with Leighton reagent). In the next step the addi- tion of a protection group for the new hydroxy group is performed. A double bond isomerisation is performed (Grubbs reaction), followed by a Swern oxi- dation. Furthermore, a Wittig reaction is performed and a Z-vinyl iodide is ob- tained which is finally selectively deprotected. Now, precursor of formula 18 is prepared, as shown in Scheme 3.
Figure imgf000023_0001
In the following Scheme 4 the synthesis of the second precursor for the syn- thetic method for the disorazole according to the present invention is de- scribed. The second precursor, named as oxazole fragment, is synthesized starting with ß-hydroxy ester of formula 19. The first step is an O-methylation reaction, followed by ozonolysis. The next step is performed as a Wittig reac- tion, followed by a hydrolysation of the ester obtaining product of formula 25. In the next step, L-serin methyl ester is reacted with compound of formula 25 to form the respective amide. In the following step, a cyclisation of the amide according to formula 26 is performed and this results to an oxazoline deriva- tive. In the next step, the oxazoline is oxidized in order to obtain the oxazole derivative according to formula 28. The protective group in the compound of formula 28 is then removed and compound of formula 29 is obtained. This compound will be used for the final reaction as one of the starting materials indicated as compound of Formula 30a. The compound of formula 30a is a combination of compounds of formula 29 and 30, which differ from each other in the ester function of the carboxyl group. Finally, compound of formula 29 is saponificated to remove the methyl group from the ester group in the compound of formula 29. Now is final product of formula 30 is obtained. According to the invention, compounds of formula 29 and formula 30 will be used in combination with the compound of formula 18 for the final reaction steps to obtain the final product disorazole of formula 37.
Figure imgf000025_0001
Figure imgf000026_0001
Now, the two precursors, namely the compounds of formula 30 and formula 29 are obtained and will be used in the final strategy for the production of dis- orazole named as compound of formula 37. Now, in Scheme 5 the final strategy is described in detail.
Figure imgf000027_0001
Figure imgf000028_0001
The total synthesis of disorazole of the formula 37 is performed in the follow- ing steps. The compounds of formula 18 and formula 29 are coupled. Especially pre- ferred is the use of a Sonogashira reaction. Compound of formula 31 is pro- duced and an esterification with compound of formula 30 is performed in the next step, wherein compound of formula 32 is obtained. In the next step, compound of formula 32 and compound of formula 18 are coupled, especially preferred also with a Sonogashira reaction. The reaction produces the open- chained compound of formula 33. The next steps of the reactions according to Scheme 5 perform the cyclisa- tion of compound of formula 33, forming the final product, disorazole of for- mula 37. In the first step, a saponification of the methyl ester in compound of formula 33 is performed and compound of formula 34 is obtained. With compound of formula 34 a macrolactonisation is performed, wherein the Yamaguchi reac- tion is preferred. With the obtained compound of formula 35 a hydrogenation of the triple bonds is performed and compound of formula 36 is obtained. In the final step, the protective groups are removed and the final product ac- cording to the invention, disorazole C1 of formula 37 is obtained. Now in Scheme 6 a further advantageous strategy for the production of diso- razoles according to the present invention is described in detail. The precur- sor 17a, comprising protective groups PG1 and PG2 is described already in the complete description. This precursor is also named as general formula II. The same applies to precursor 30a, which is also described herein as com- pound of formula I. In reaction Scheme 6 the carboxyl group is methylated. All reactive groups are protected so that the step a), as indicated in Scheme 6, is performed as a Sonogashira reaction, as described in Scheme 5. In con- trast to Scheme 5, the product 40 is now reacted in two different steps in or- der to obtain the products 41 and 42. The products 41 and 42 differ from each other only in one reactive group. In step b) , as indicated in Scheme 6, which is a simple demethylation step, Rx, the methyl group is removed and changed into hydrogen, so that a free hydroxyl group is present in the com- pound of formula 41. In step c) , as indicated in Scheme 6, compound of for- mula 40 is demethylated in a simple saponification step and results in a free carboxylic group as indicated in the compound of formula 42. Now in step d), as indicated in Scheme 6, a Yamaguchi reaction is performed as a lactoniza- tion of compounds of formula 41 and 42 into compound of formula 43. In the final steps e) and f), as indicated in Scheme 6, the protective groups are re- moved as already shown in steps b) and c) , as indicated in Scheme 6. The final cyclization reaction to obtain the disorazole according to the present in- vention is performed, for example, in the same way as shown in Scheme 5 , as indicated above.
Figure imgf000030_0001
For a person skilled in the art it is clear that all possible diastereomers of dis- orazoles according to general formula III of formula 37 can be obtained, when starting the reactions with the respective diastereomeric precursors of formula I and formula II, as described above. In the presented Schemes 1 to 6 different protective groups are indicated. It is clear for a person skilled in the art that other protective groups may be used. Especially preferred are the following protective groups: MOM (meth- oxymethyl), MEM ((2-methoxyethoxy)phenyl), THP (tetrahydropyranyl), TMS (trimethylsilyl), TES (triethylsilyl), TIPS(triisopropylsilyl), TBS (tert-butyldime- thylsilyl), TBDPS (tert-butyldiphenylsilyl), OAc (O-Acyl). Furthermore, in the Schemes 1 to 6 name reactions are mentioned. It is also clear for persons skilled in the art that other reactions or name reactions may be used according to the invention. Details of the performed reactions are disclosed in the examples as pre- sented herein. Complete chemical names of the compounds of the given for- mulas are also disclosed in the examples as given herein. It has to be pointed out that the above described synthetic pathways can be modified by persons skilled in the art to produce all disorazoles and their ana- logues according to the present invention. The most important feature of the present invention is the use of two precursors as described as compounds of formula I and II. These compounds are each used twice in different steps.
Examples The following examples disclose the preferred embodiments of the present invention. It should be appreciated by those of skill in the art that the tech- niques disclosed in the examples which follow represent techniques discov- ered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are dis- closed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Synthesis of compounds of the invention General: Solvents were dried by standard procedures and redistilled under N2 atmosphere prior to use. All organometallic reactions were run under nitro- gen. The products were purified by flash chromatography on Merck silica gel 60 (40-63 µm). Mass spectra were recorded on Finnigan MAT 95 and Waters Xevo G2-TOF spectrometers. NMR spectra were recorded on Brucker AVIII 400 and Brucker AVI 600 spectrometers. Optical rotations were recorded with a Perkin-Elmer 341 polarimeter.
Example 1: (S)-(+)-Mandelic acid methyl ester (1)
Figure imgf000033_0001
To a solution of (S)-(+)-Mandelic acid (57.13 g, 376 mmol, 1 eq) in MeOH (300 mL), concentrated sulfuric acid (600 µL, 11.3 mmol, 0.03 eq) was added and the mixture was refluxed for 4 h. The reaction was quenched with K2CO3 (1.04 g, 7.52 mmol, 0.02 eq) in 1.2 mL of water and the MeOH was evapo- rated in vacuo. Then Et2O (300 mL) was added and the solid was filtered off; the mixture was concentrated and crystallized from hexane (75 mL) to furnish ester 1 (54.9 g, 330.72 mmol, 88%) as a white solid. General Data: C9H10O3; FW: 166.06; Mp: 56-58°C; TLC: Rf= 0.35 (Pen- tane/Et2O 1:1); UV (+); Vanillin: yellow. 1H-NMR (600 MHz, CDCl3): δ (ppm): 7.36-7.34 (d, 2H); 7.31-7.30 (d, 2H); 7.27-7.26 (dd, 1H); 5.11 (s, 1H), 3.69 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 174.17; 138.22; 128.65; 128.55; 126.65; 126.61; 72.89 (C-2); 53.09.
Example 2: (S)-(-)-1,1,2-Triphenyl-1,2-ethandiol (2)
Figure imgf000034_0001
To a solution of Phenyl magnesium bromide 3 M in Et2O (200 mL, 600 mmol, 5.0 eq), ester 1 (20 g, 120.36 mmol, 1 eq) in Et2O (120 mL) and THF (12 mL) was added dropwise at 0°C at such a rate that the temperature does not rise above 10°C (90 min required). The mixture was allowed to slowly warm to room temperature overnight and then refluxed for 1 h. After cooling to room temperature, the mixture was carefully poured into ice (200 g) and HCl 2 M was added dropwise to adjust the pH value to 4. The mixture was stirred for 1 h at room temperature and then the organic layer was separated. The aque- ous phase was extracted with CH2Cl2 (3x200 mL) and the combined organic extracts were washed with NaHCO3, dried over MgSO4 and concentrated in vacuo. Crystallization of the residue from methanol (70 mL) afforded diol 2 (24.1 g, 83 mmol, 69%) as a white needle-shaped solid. General Data: C20H18O2; FW: 290.13; Mp: 123-127°C; [α]
Figure imgf000034_0002
= -125.5 (c = 1.0, CHCl3); TLC: Rf= 0.25 (Pentane/Et2O 2:1); UV (+); Vanillin: yellow. 1H-NMR (600 MHz, CDCl3): δ (ppm): 7.65-7.61 (m, 2H); 7.40-7.00 (m, 13H); 5.55 (s, 1H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 145.12; 143.36; 138.81; 128.47; 128.09; 127.72; 127.64; 127.63; 127.48; 127.40; 127.30; 127.12; 127.02; 126.74; 126.19; 80.77; 50.89. Example 3: (S)-(-)-2-Hydroxy-1,2,2-triphenylethylacetate [(S)-HYTRA] (3)
Figure imgf000035_0001
Acetyl chloride (7.85 mL, 110.39, 1.33 eq) in CH2Cl2 (20 mL) was added dropwise at 0°C to a solution of diol 2 (24.1 g, 83 mmol, 1 eq) in CH2Cl2 (220 mL) and Pyridine (10.74 mL, 132.8 mmol, 1.6 eq), at such a rate that the temperature does not rise above 5°C. The mixture was stirred for 16 h at room temperature. Then water (100 mL) was added and the mixture was stirred for 10 min. The mixture was concentrated in vacuo until second phase CH2Cl2 was no longer observed. The white precipitate was filtered by suction, washed with water and HCl and dried by suction for 2-3 h. Then the solid was dissolved in hot toluene and the azeotrope was removed by atmospheric dis- tillation. The mixture was allowed to cool to room temperature over several hours and then cooled to 0°C for 1 h. The precipitate was collected on a filter and recrystallized from acetone to furnish (S)-HYTRA 3 (23.2 g, 69.8 mmol, 84 %) as a white solid. General Data: C22H20O3; FW: 332.14; Mp: 249-251°C; [α]
Figure imgf000035_0002
= -215.5 (c = 1.0, Pyridine); TLC: Rf= 0.50 (Pentane/Et2O 2:1); UV (+). 1H-NMR (600 MHz, CDCl3): δ (ppm): 7.50-7.48 (m, 2H); 7.31-6.98 (m, 13H); 6.61 (s, 1H); 2.76 (s, 1H); 1.92 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 169.73; 144.82; 142.64; 135.82; 128.44; 128.38; 127.93; 127.79; 127.47; 127.35; 127.01; 126.41; 126.30; 126.17; 126.12; 125.03; 80.30; 78.50; 21.14. Example 4: Ethyl 3-hydroxy-2,2-dimethylpentanoate (4)
Figure imgf000036_0001
n-BuLi (133 mL, 332.38 mmol, 1.1 eq, 2.5 M solution in hexane) was added dropwise at -78°C to a solution of diisopropylamine (46.5 mL, 332.37 mmol, 1.1 eq) in THF (300 mL). This LDA solution was stirred for 30 min at 0°C and then cooled to -78°C. Ethyl isobutyrate (40.6 mL, 302.16 mmol, 1 eq) dis- solved in THF (58 mL) was added dropwise and the mixture was stirred for 1 h at -78°C. Propionaldehyde (23.8 mL, 332.38 mmol, 1.1 eq) was added dropwise at -78°C and then the bath was removed and the mixture was stirred for 30 min between -50°C and -10°C. The reaction was quenched by dropwise addition of saturated aqueous NH4Cl solution (300 mL) and the or- ganic layer was separated and the aqueous phase was extracted with Et2O (3x200 mL). The combined organic extracts were dried over MgSO4 and con- centrated in vacuo. Purification of the residue by vacuum distillation through a short Vigreux column afforded β-hydroxy ester 4 (48.97 g, 281.25 mmol, 93%) as a colorless liquid. General Data: C9H18O3; FW: 174.13; Bp: 105°C (5 mbar); TLC: Rf = 0.35 (Pentane/Et2O 2:1); UV (-); Vanillin: light blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 4.16 (q, J = 7.27 Hz, J = 21.46 Hz, 2H); 3.45 (dd, J = 10.68, J = 2.02, 1H); 1.54-1.48 (m, 2H); 1.25 (t, J = 7.34 Hz, 3H); 1.17 (s, 3H,); 1.15 (s, 3H); 0.95 (t, J = 7.77 Hz, 3H). 13C-NMR (151MHz, CDCl3): δ (ppm): 177.80; 78.39; 60.62; 47.02; 24.58; 20.42; 14.15; 11.29. MS (EI): m/z (%): 175.07 (100) [M+H]+, 173.06 (68), 170.05 (26), 169.04 (22). HR-MS: calculated: 174.1329, found: 175.1329 [M+H]+, 197.1152 [M+Na+]+. Example 5: Ethyl (E)-2,2-dimethyl-3-pentenoate (5)
Figure imgf000037_0001
Hydroxy ester 4 (48.97 g, 281.25 mmol) was refluxed with Sicapent (70 g) in Cyclohexane (250 mL) for 30 min. The solvent was removed by atmospheric distillation and vacuum distillation of the residue afforded ester 5 (29.85 g, 191.25 mmol, 68%) as a colorless liquid. General Data: C9H16O2; FW: 156.12; Bp: 55-60°C (10 mbar); TLC: Rf= 0.75 (Pentane/Et2O 2:1); UV (-); Vanillin: blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 5.64 (dq, J = 15.72 Hz, J = 1.6 Hz 1H); 5.53-5.47 (m, 1H); 4.14 (qd, J = 7.09 Hz, J = 1.18 Hz, 2H); 1.68 (dd, J = 6.24 Hz, J = 1.58 Hz 3H), 1.27 (s, 6H); 1.25 (t, J = 7.15 Hz, 3H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 176.83; 135.61; 123.33; 60.54; 44.02; 25.13; 18.03; 14.15. MS (EI): m/z (%): 156.07 (100) [M]+, 141.05 (77), 116.03 (54), 110.02 (21). HR-MS: calculated: 156.1145, found: 156.1145. Example 6: (E)- 2,2-dimethyl-3-penten-1-ol (6)
Figure imgf000037_0002
To a solution of ester 5 (16.37 g, 104.94 mmol, 1 eq) in THF (150 mL), LiAlH4 (7.98 g, 209.87 mmol, 2 eq) was added and the mixture was refluxed for 2 h. After cooling to 0°C, Et2O (100 mL) was added and the reaction was quenched by dropwise addition of water (10 mL). The mixture was stirred for 30 min at room temperature until a white precipitate was formed, which was filtered off by suction through Celite and washed with Et2O (3x200 mL). The filtrate and the washings were combined and concentrated in vacuo to furnish crude alcohol 6 (8.97 g, 78.7 mmol, 75%) as a colorless liquid, which was used for the preparation of aldehyde 7 without further purification. General Data: C7H14O; FW: 114.10; Bp: 152-160°C; TLC: Rf= 0.35 (Pen- tane/Et2O 2:1); UV (-); dark blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 5.50-5.44 (m, 1H); 5.35 (dq, J = 15.68 Hz, J = 1.29 Hz, 1H); 3.28 (s, 2H); 1.69 (d, J = 6.22 Hz, 3H); 1.65 (s, 1H); 0.977 (s, 6H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 137.76; 124.14; 71.6; 38.33; 46.21; 23.92; 18.23. HR-MS: calculated: 114.10, found: 115.11 [M+H]+. Example 7: (E)-2,2-dimethyl-3-pentenal (7)
Figure imgf000038_0001
DMSO (11.2 mL, 157.4 mmol, 2.0 eq) in CH2Cl2 (45 mL) was added drop- wise at -78°C to a stirred solution of (COCl)2 (8.1 mL, 94.44 mmol, 1.2 eq) in CH2Cl2 (210 mL). The mixture was stirred for 10 min at -78°C. The crude (E)- 2,2-dimethyl-3-penten-1-ol 6 (8.97 g, 78.7 mmol, 1 eq) dissolved in CH2Cl2 (60 mL) was added dropwise at -78°C and the mixture was stirred for 1 h at - 78°C. The reaction was quenched by dropwise addition of NEt3 (54.6 mL, 393.5 mmol, 5.0 eq) and the mixture was warmed to room temperature over 45 min. Water was added (250 mL) and the mixture was stirred for 10 min. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (3x150 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Vacuum distillation of the residue afforded alde- hyde 7 (6.6 g, 79.02 mmol, 75%) as a colorless liquid. General Data: C7H14O; FW: 112.09; Bp: 127-128°C; TLC: Rf= 0.80 (Pen- tane/Et2O 5:1); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 9.32 (s, 1 H); 5.58-5.48 (m, 1H); 5.36 (dq, J = 15.76 Hz, J = 1.69 Hz, 1H); 1.71 (dd, J = 6.41 Hz, J = 1.61 Hz, 3H); 1.14 (s, 6H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 202.92; 132.46; 127.06; 46.21; 21.49; 18.3. Example 8: (1S)-2-Hydoxy-1,2,2-triphenylethl (3S,5E)-3hydoxy-4,4-dimethyl-5-hep- tenoate (8)
Figure imgf000039_0001
n-BuLi (22.5 mL, 56.32 mmol, 2.2 eq, 2.5 M solution in hexane) was added dropwise at -78°C to a solution of diisopropylamine (7.9 mL, 56.32 mmol, 2.2 eq) in THF (80 mL). This LDA solution was stirred for 30 min at 0°C and then added dropwise to a solution of (S)-HYTRA 3 (8.5 g, 25.6 mmol, 1 eq) in THF (150 mL) at -78°C. The mixture was stirred for 1 h at 0°C. The resulting or- ange-red solution was cooled to -78°C and a solution of aldehyde 7 (3.44 mg, 30.7 mmol, 1.2 eq) in THF (7 mL) was added dropwise. The mixture was stirred for 2h30min at -78°C. The reaction was quenched by dropwise addi- tion of saturated aqueous NH4Cl solution (150 mL) and the mixture was al- lowed to warm to room temperature over 30 min. The organic layer was sep- arated and the aqueous phase was extracted with CH2Cl2 (3x100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (pentane/Et2O 3:1) afforded β-hydroxy ester 8 (8.75 g, 19.71 mmol, 77%) as a colorless solid. General Data: C29H32O4; FW: 444.23; Melting point: 120 - 126°C; [α] = -
Figure imgf000039_0002
167.8 (c = 1.0, CHCl3); TLC: Rf= 0.45 (Pentane/Et2O 2:1); UV (+); Vanillin: green. 1H-NMR (600 MHz, CDCl3): δ (ppm): 7.61-7.53 (m, 2H); 7.39-7.33 (m, 2H); 7.31-7.26 (m, 1H); 7.22-7.03 (m, 10H); 6.71 (s, 1H); 5.43-5.45 (m, 1H); 5.26 (dd, J = 15.72, J = 1.31 Hz, 1H); 3.51 (dd, J = 10.38 Hz, J = 2.18 Hz, 1H); 2.79 (s, 1H); 2.36 (dd, J = 15.81, Hz, J = 2.07 Hz, 1H); 2.24 (dd, J = 16.29 Hz, J = 10.35 Hz, 1H); 1.98 (s, 1H); 1.65 (dd, J = 6.08 Hz, J = 1.28 Hz, 3H); 0.92 (s, 3H); 0.91 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 172.23; 144.61; 142.58; 137.02; 135.42; 128.41; 128.35; 127.99; 127.83; 127.54; 127.36; 127.11; 127.28; 127.20; 123.86; 80.33; 78.96; 74.86; 40.03; 37.35; 23.62; 22.68; 18.26. MS (EI): m/z (%): 911.45 (40) [2M+Na+]+, 467.22 (97) [M+Na+]+, (77), 444.23 (˂0.4), 273.13 (100), 255.12 (18), 195.08 (31). HR-MS: calculated: 444.2298, found: 467.2198 [M+Na+]+. Example 9: (3S,5E)-4,4-dimethyl-5-heptene-1,3-diol (9)
Figure imgf000040_0001
8 LiAlH4 (5.2 g, 137.97 mmol, 7.0 eq) was added portionwise to a refluxing so- lution of β-hydroxy ester 13 (8.75 g, 19.71 mmol, 1 eq) in Et2O (210 mL), dur- ing a period of 2 h. Reflux was continued for 30 min. After cooling to 0°C, the reaction was quenched by dropwise addition of water (10 mL). Then Et2O (150 mL) and water (0.95 mL) was and the mixture was stirred for 30 min at room temperature until a white precipitate was formed. The precipitate was filtered off by suction through Celite and washed with Et2O (4x100 mL). The filtrate and the washings were combined and concentrated in vacuo. Purifica- tion of the residue by flash chromatography (pentane/Et2O 2:1 to pure Et2O) afforded diol 9 (2.5 g, 15.77 mmol, 80%) as a colorless oil and (S)-(-)-1,1,2- triphenyl-1,2-ethandiol 2 (5.1 g, 17.74 mmol, 90 %) General Data: C9H18O2; FW: 158.13; [α] = -7.28 (c = 0.7, CHCl3); TLC: Rf=
Figure imgf000040_0002
0.30 (Et2O); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 5.52-5.43 (m, 1 H); 5.35 (dq, J = 15.69 Hz, J = 1.29 Hz, 1H); 3.86-3.76 (m, 2H); 3.48 (dd, J = 10.49 Hz, J = 2.16 Hz, 1H); 2.39 (s, 1H); 1.68 (dd, J = 5.96 Hz, J = 1.23 Hz, 3H); 1.74-1.66 (m, 1H); 1.74-1.66 (m, 1H); 1.62-1.52 (m, 1H); 0.98 (s, 6H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 137.55; 124.51; 78.88; 62.56; 40.71; 32.62; 23.67; 22.16; 18.30. MS (EI): m/z (%): 181.1207 (100), 158.13 (˂0.4), 123.12 (42). HR-MS: calculated: 158.1307, found: 181.1207 [M+Na+]+. Example 10: (S,E)-3,3,9,9-tetraethyl-5-(2-methylpent-3-en-2-yl)-4,8-dioxa-3,9-disilaun- decane (10)
Figure imgf000041_0001
To a solution of diol 9 (1.96 g, 12.4 mmol, 1 eq) in CH2Cl2 (120 mL), 2,6- Lutidine (5.8 mL, 49.6 mmol, 4 eq) and TESOTf (8.4 mL, 37.18 mmol, 3 eq) were sequentially added dropwise at -78°C. The mixture was stirred for 30 min at -78°C and for 1 h at 0°C. Saturated aqueous NaHCO3 solution (100 mL) was added and the layers were separated. The aqueous phase was ex- tracted with CH2Cl2 (3x80 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (pure pentane) furnished compound 9 (4.74 g, 12.28 mmol, 99%) as a colorless liquid. General Data: C21H46O2Si2; FW: 386.3; [α] = -7.25 (c = 0.4, CHCl3
Figure imgf000041_0002
); TLC: Rf= 0.20 (pentane); UV (-); Vanillin: black. 1H-NMR (600 MHz, CDCl3): δ (ppm): 5.43 (dq, J = 15.67 Hz, J = 1.22 Hz, 1H); 5.38-5.29 (m, 1H); 3.71-3.63 (m, 1H); 3.61-3.53 (m, 1H); 3.46 (dd, , J = 8.17 Hz, J = 2.7 Hz); 1.65 (dd, J = 5.93 Hz, J = 1.19, 3H); 1.77-1.68 (m, 1H); 1.53-1.43 (m, 1H); 1.00-0.89 (m, 18H); 0.96 (s, 3H); 0.92 (s, 3H); 0.66-0.47 (m, 12H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 139.29; 121.46; 76.87; 60.87; 41.12; 36.71; 24.63; 22.90; 18.30; 7.14; 6.81; 6.79; 6.41; 5.47; 4.46. Example 11: (S)-2,2-dimethyl-3,5-bis((triethylsilyl)oxy)pentanal (11)
Figure imgf000042_0001
A stream of ozone in oxygen was bubbled through a solution of compound 10 (4.74 g, 12.28 mmol, 1 eq) in CH2Cl2 (400 mL) at -78°C until the blue color of the solution persisted. Then PPh3 (3.86 g, 14.73 mmol, 1.2 eq) was added at -78°C and the mixture was allowed to slowly warm to room temperature over 4 h. The crude was concentrated in vacuo and purified by flash chromatog- raphy (pentane/Et2O 200:1 to 50:1) to furnish aldehyde 11 (2.75 g, 7.36 mmol, 60 %) as a colorless liquid. General Data: C19H42O3Si2; FW: 374.27; [α] = +10.11 (c = 0.9, CHCl3);
Figure imgf000042_0002
TLC: Rf= 0.35 (Pentane/Et2O 50:1); UV (-); Vanillin: violet. 1H-NMR (600 MHz, CDCl3): δ (ppm): 9.57 (s, 1H); 3.99 (dd, J = 8.13 Hz, J = 3.02 Hz, 1H); 3.71-3.58 (m, 2H); 1.74-1.64 (m, 1H); 1.62-1.52 (m, 1H); 1.04 (s, 3H); 1.00 (s, 3H); 0.98-0.908 (m, 18H); 0.65-0.54 (m, 12H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 206.6; 73.21; 59.53; 51.09; 36.33; 18.88; 17.34; 6.97; 6.78; 5.35; 4.43.
Example 12: (4S,6S)-5,5-dimethyl-6,8-bis((triethylsilyl)oxy)oct-1-en-4-ol (12)
Figure imgf000043_0001
A solution of Leighton reagent (4.74 g, 8.58 mmol, 1.2 eq) in CH2Cl2 (20 mL) was added to a solution of aldehyde 11 (2.67 g, 7.15 mmol, 1 eq) in CH2Cl2 (50 mL). Then Sc(OTf)3 (175 mg, 0.375 mmol, 0.05 eq) was added and the mixture was stirred for 24 h at room temperature. TBAF trihydrate (2.26 g, 7.15 mmol, 1 eq) was added and the mixture was stirred for 30 min at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (pentane/Et2O 50:1, then pentane/EtOAc/NEt31:1:0.1) to furnish the allylic alcohol (2.36 g, 5.65 mmol, 80%) as a colorless liquid and the recovered diamine (3.64 g, 8.08 mmol, 87 %) as a yellow paste. General Data: C22H48O3Si2; FW: 416.31; [α] 0
Figure imgf000043_0002
= -4.2 (c = 0.5, CHCl3); TLC: Rf= 0.2 (Pentane/Et2O 50:1); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 5.94-5.86 (m, 1H); 5.13-5.05 (m, 2H); 3.79 (dd, J = 6.76 Hz, J = 2.79 Hz, 1H); 3.74 (m, 1H); 3.65 (m, 1H); 3.51 (d, J = 10.49 Hz, 1H); 2.73 (s, 1H); 2.31-2.25 (m, 1H); 2.1-2.02 (m, 1H); 2.01-1.93 (m, 1H); 1.54-1.48 (m, 1H); 0.993-0.923 (m, 18H); 0.897 (s, 3H); 0.781 (s, 3H); 0.65-0.54 (m, 12H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 137.22; 116.51; 75.64; 75.41; 61.24; 42.44; 36.46; 36.37; 18.72; 18.49; 7.08; 6.72; 5.51; 4.28.
Example 13: (5S,7S)-5-allyl-11,11-diethyl-6,6-dimethyl-7-((triethylsilyl)oxy)-2,4,10-tri- oxa-11-silatridecane (13)
Figure imgf000044_0001
MOMCl (1.3 mL, 17 mmol, 3 eq) was added dropwise at 0°C to a solution of allylic alcohol 12 (2.36 g, 5.67 mmol, 1 eq), DIPEA (3 mL, 17 mmol, 3 eq) and DMAP (207 mg, 1.7 mmol, 0.3 eq) in CH2Cl2 (60 mL). The mixture was stirred overnight at 45°C. Evaporation of the solvent and purification of the residue by flash chromatography (Pen/Et2O 60:1) afforded the protected al- cohol (2.4 g, 5.21 mmol, 92 %) as a colorless liquid. General Data: C24H52O4Si2; FW: 460.34; [α]
Figure imgf000044_0002
= -10.67 (c = 0.75, CHCl3); TLC: Rf= 0.5 (Pentane/Et2O 50:1); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 5.95-5.87 (m, 1H); 5.09-4.98 (m, 2H); 4.61 (q, J = 6.61 Hz, 2H); 3.74-3.68 (m, 2H); 3.63.3.57 (m, 1H); 3.48 (dd, J = 8.59 Hz, J = 2.85, Hz 1H); 2.48-2.41 (m, 1H); 2.23-2.14 (m, 1H); 1.91-1.83 (m, 1H); 1.55-1.48 (m, 1H); 1.00-0.923 (m, 18H); 0.917 (s, 3H); 0.811 (s, 3H); 0.655-0.565 (m, 12H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 137.22; 115.95; 98.09; 83.46; 74.54; 60.86; 56.11; 43.39; 36.17; 20.78; 19.26; 7.14; 6.79; 5.63; 4.43.
Example 14: (3S,5S,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl)oxy)non-7- en-1-ol (15)
Figure imgf000045_0001
A solution of protected triol 13 (2.3 g, 5 mmol, 1 eq) and Grubbs II (212 mg, 0.250 mmol, 0.05 eq) in MeOH was stirred overnight at 60°C. The mixture was then concentrated in vacuo and the residue was filtered on a pad of sil- ica gel (Pen/Et2O 1:1). The filtrate was concentrated in vacuo affording a mix- ture of 15 (80%) and 14 (15%) as a colorless liquid, which was used in the next step without further purification. General Data (14): C25H52O4Si2; FW: 460.34; [α]2
Figure imgf000045_0002
= -44.0 (c = 0.2, CHCl3); TLC: Rf= 0.5 (Pentane/Et2O 50:1); UV (-); Vanillin: dark blue. 1H-NMR (14) (600 MHz, CDCl3): δ (ppm): 5.64-5.54 (m, 1H); 5.31 (qd, J = 7.79 Hz, J = 1.69 Hz, 1H); 4.66 (d, J = 6.58 Hz, 1H); 4.43 (d, J = 6.58 Hz, 1H); 3.86 (d, J = 8.85 Hz, 1H); 3.75 (dd, J = 8.62 Hz, J = 2.38 Hz, 1H); 3.73.3.55 (m, 2H); 3.35 (s, 3H); 1.94-1.82 (m, 1H); 1.71 (dd, J = 6.37 Hz, J = 1.54 Hz, 3H) 1.63-1.53 (m, 1H); 1.01-0.878 (m, 18H); 0.948 (s, 3H); 0.939 (s, 3H); 0.668-0.540 (m, 12H). 13C-NMR (14) (151 MHz, CDCl3): δ (ppm): 130.63; 127.94; 93.43; 81.11; 74.3; 61.09; 55.74; 42.18; 35.74; 20.10; 19.35; 17.79; 7.14; 6.77; 5.63; 4.37. General Data (15): C18H38O4Si; FW: 346.25; [α]
Figure imgf000045_0003
= -69.0 (c = 0.8, CHCl3); TLC: Rf= 0.3 (Pentane/Et2O 3:1); UV (-); Vanillin: dark blue. 1H-NMR (15) (600 MHz, CDCl3): δ (ppm): 5.64-5.54 (m, 1H); 5.31 (qd, J = 6.70 Hz, J = 1.64 Hz, 1H); 4.62 (d, J = 6.46 Hz, 1H); 4.43 (d, J = 6.46 Hz, 1H); 3.87 (dd, J = 8.68 Hz, J = 2.59 Hz, 2H); 3.81 (d, J = 8.50 Hz, 1H); 3.79- 3.72 (m, 1H); 3.71-3.62 (m, 1H); 3.33 (s, 3H); 1.95-1.84 (m, 1H); 1.71 (dd, J = 6.48 Hz, J = 1.53 Hz, 3H); 1.67-1.57 (m, 1H); 1.00-0.932 (m, 9H); 0.923 (s, 3H); 0.736 (s, 3H); 0.678-0.583 (m, 6H). 13C-NMR (15) (151 MHz, CDCl3): δ (ppm): 130.84; 127.77; 93.64; 81.75; 74.46; 60.85; 55.67; 42.06; 35.34; 20.10; 19.10; 17.82; 7.11; 5.60. Example 15: (3S,5S,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl)oxy)oct-6- enal (16)
Figure imgf000046_0001
DMSO (0.780 mL, 11 mmol, 2 eq) in CH2Cl2 (5 mL) was added dropwise to a solution of oxalyl chloride (0.644 mL, 7.5 mmol, 1.2 eq) in CH2Cl2 (20 mL) at - 78°C. The mixture was stirred for 10 min at -78°C and then the crude 14 + 15 dissolved in CH2Cl2 (5 mL) was added dropwise. The reaction was stirred for 1 h at -78°C, quenched by dropwise addition of NEt3 (3.5 mL, 25 mmol, 5 eq) and then warmed to room temperature over 45 min. H2O (30 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3x20 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by flash chromatography (Pen/Et2O 10:1) afforded aldehyde 16 (1.33 g, 3.86 mmol, 77%) as a colorless liquid. General Data: C18H36O4Si2; FW: 344.24; [α]
Figure imgf000046_0002
= -54.87 (c = 0.8, CHCl3); TLC: Rf= 0.3 (Pentane/Et2O 10:1); UV (-); Vanillin: grey. 1H-NMR (600 MHz, CDCl3): δ (ppm): 9.83 (dd, J = 3.00 Hz, J = 1.21 Hz, 1H); 5.66-5.56 (m, 1H); 5.29 (qd, J = 7.60 Hz, J = 1.66 Hz, 1H); 4.64 (d, J = 6.71 Hz, 1H); 4.41 (d, J = 6.71 Hz, 1H); 4.31 (dd, J = 7.05 Hz, J = 3.59 Hz, 1H); 3.78 (d, J = 8.70 Hz, 1H); 3.33 (s, 3H); 2.75 (qd, J = 16.71, Hz, J = 1.33 Hz, 1H); 2.58 (qd, J = 16.23, Hz, J = 3.01 Hz, 1H); 1.72 (dd, J = 6.48 Hz, J = 1.67 Hz, 3H); 0.965 (s, 3H); 0.957-0.907 (m, 9H); 0.767 (s, 3H); 0.640-0.545 (m, 6H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 202.75; 131.42; 127.20; 93.26; 81.37; 72.01; 55.87; 47.82; 42.06; 20.05; 19.74; 6.99; 5.35. Example 16: (5S,7S)-9,9-diethyl-7-((Z)-3-iodoallyl)-6,6-dimethyl-5-((E)-prop-1-en-1-yl)- 2,4,8-trioxa-9-silaundecane (17)
Figure imgf000047_0002
NaHMDS (1 M in THF, 4.2 mL, 4.2 mmol, 1.5 eq) was added dropwise at 0°C to a solution of IMePPh3I (2.22 g, 4.2 mmol, 1.5 eq) in THF (30 mL). The red solution was stirred for 10 min at room temperature and then cooled to -78°C. DMPU (2.5 mL, 20.93 mmol, 7.5 eq) was added dropwise, followed by alde- hyde 16 (960 mg, 2.79 mmol, 1 eq) in THF (7 mL). The mixture was stirred for 1 h at -78°C and 30 min at room temperature. Saturated NH4Cl solution was added and the aqueous phase was extracted with Et2O (3x25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Pen/Et2O 100:1) giving the Z Iodide 17 (875 mg, 1.87 mmol, 67%) as a slightly yellow liquid. General Data: C19H37IO3Si; FW: 468.16; [α]
Figure imgf000047_0001
= -30.133 (c = 0.75, CHCl3); TLC: Rf= 0.25 (Pentane/Et2O 100:1); UV (-); Vanillin: black. 1H-NMR (600 MHz, CDCl3): δ (ppm): 6.36 (q, J = 7.43 Hz, 1H); 6.21 (dt, J = 7.36 Hz, J = 1.67 Hz, 1H); 5.69-5.56 (m, 1H); 5.33 (qd, J = 6.69 Hz, J = 1.62 Hz, 1H); 4.68 (d, J = 6.60 Hz, 1H); 4.45 (d, J = 6.60 Hz, 1H); 3.88 (t, J = 5.03 Hz, 1H); 3.86 (d, J = 3.80 Hz, 1H); 3.36 (s, 3H); 2.44-2.38 (m, 2H); 1.73 (dd, J = 6.52 Hz, J = 1.57 Hz, 3H); 1.02-0.922 (m, 9H); 0.941 (s, 3H); 0.769 (s, 3H); 0.658-0.559 (m, 6H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 140.20; 131.02; 127.77; 93.49; 82.57; 81.41; 75.63; 55.90; 42.65; 38.61; 20.16; 19.60; 17.85; 7.12; 5.57. Example 17: (1Z,4S,6S,7E)-1-iodo-6-(methoxymethoxy)-5,5-dimethylnona-1,7-dien-4- ol (18)
Figure imgf000048_0001
CSA (93 mg, 0.4 mmol, 0.2 eq) was added at 0°C to a solution of Z Iodide 17 (940 mg, 2 mmol, 1 eq) in CH2Cl2 (50 mL) and MeOH (50 mL). The mixture was stirred for 1 h at 0°C without N2. Saturated NaHCO3 solution (100 mL) was added and the layers were separated. The aqueous phase was ex- tracted with CH2Cl2 (3x100 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was puri- fied by flash chromatography (Pen/Et2O 3:1) giving deprotected Iodide 18 (601 mg, 1.7 mmol, 85%) as a slightly yellow liquid. General Data: C13H23IO3; FW: 354.07; [α]
Figure imgf000048_0002
= -52.7 (c = 1.00, CHCl3); TLC: Rf= 0.3 (Pentane/Et2O 3:1); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 6.39 (q, J = 6.68 Hz, 1H); 6.28 (dt, J = 7.24 Hz, J = 1.18 Hz, 1H); 5.74-5.60 (m, 1H); 5.32 (qd, J = 6.34 Hz, J = 1.49 Hz, 1H); 4.72 (d, J = 6.65 Hz, 1H); 4.46 (d, J = 6.65 Hz, 1H); 3.89 (d, J = 9.12 Hz, 1H); 3.66 (dd, J = 10.22 Hz, J = 2.74 Hz, 1H); 3.38 (s, 3H); 2.42-2.32 (m, 1H); 2.30-2.16 (m, 1H); 1.74 (dd, J = 6.46 Hz, J = 1.42 Hz, 3H); 0.980 (s, 3H); 0.826 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 139.48; 132.59; 126.83; 93.01; 84.89; 83.50; 77.43; 56.03; 40.94; 37.31; 21.62; 17.87; 15.85. Example 18: tert-Butyl (R)-3-hydroxypent-4-enoate (19)
Figure imgf000049_0001
Vinyl acetate (16 mL, 174.18 mmol, 3 eq) was added to a solution of racemic tert-Butyl 3-hydroxypent-4-enoate (10 g, 58.06 mmol, 1 eq) in pentane (200 mL). Then Amano Lipase PS (6 g) and 4Â molecular sieves (9.5 g) were added and the mixture was stirred for 24 h at 30°C. The solids were filtered on paper and washed with Et2O; the filtrate was concentrated in vacuo and the residue purified by flash chromatography (Pen/Et2O 6:1 to 2:1) to afford (R)-19 (4.71 g, 27.35 mmol, 47%) as a colorless liquid and (S)-Acetate (6.04 g, 28.22 mmol, 48%). General Data: C9H16O3; FW: 172.11; [α]
Figure imgf000049_0002
= +8.9 (c = 0.55, CHCl3); TLC: Rf= 0.35 (Pentane/Et2O 2:1); UV (-); Vanillin: light blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 5.89-5.80 (m, 1H); 5.27 (dt, J = 17.19 Hz, J = 1.43 Hz, 1H); 5.11 (dt, J = 10.53 Hz, J = 1.29 Hz, 1H); 4.49-4.43 (m, 1H); 2.47 (dd, J = 16.14 Hz, J = 4.1 Hz, 1H); 2.47 (dd, J = 16.02 Hz, J = 8.35 Hz, 1H); 1.43 (s, 9H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 171.64; 138.94; 115.05; 81.34; 68.98; 42.11; 28.05. Example 19: tert-Butyl (R)-3-Methoxypent-4-enoate (21)
Figure imgf000050_0001
Proton Sponge (17.5 g, 81.86 mmol, 3 eq) and trimethyl oxonium tetra- fluoroborate (8.08 g, 54.58 mmol, 2 eq) were added to a solution of (R)-19 (4.7 g, 27.29 mmol, 1 eq) in CH2Cl2 (115 mL) and the mixture was stirred for 3 h at room temperature. The reaction mixture was then filtered through a pad of Celite and the filtrate was washed with saturated aqueous solution of NaHSO4 to remove Proton Sponge. The aqueous phase was extracted with CH2Cl2 and the organic extracts were dried over Na2SO4, filtered and concen- trated in vacuo. The residue was purified by silica gel chromatography (Pen/Et2O 20:1, then 2:1) to give 21 (3.91 g, 21.03 mmol, 77%) as a color- less liquid and unreacted alcohol (517 mg, 3.00 mmol, 11%). General Data: C10H18O3; FW: 186.13; [α] 0 = +1.1 (c = 0.55, CHCl3
Figure imgf000050_0002
); TLC: Rf= 0.30 (Pentane/Et2O 20:1); UV (-); Vanillin: dark blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 5.72-5.65 (m, 1H); 5.27 (dt, J = 17.17 Hz, J = 1.43 Hz, 1H); 5.21 (dt, J = 10.53 Hz, J = 1.29 Hz, 1H); 4.00-3.93 (m, 1H); 3.28 (s, 3H); 2.51 (dd, J = 14.85 Hz, J = 8.09 Hz, 1H); 2.36 (dd, J = 14.75 Hz, J = 5.68 Hz, 1H); 1.44 (s, 9H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 170.16; 137.22; 117.65; 80.60; 79.40; 56.49; 42.06; 28.09.
Example 20: tert-butyl (R)-3-methoxy-4-oxobutanoate (22)
Figure imgf000051_0001
A stream of O3 in O2 was bubbled through a solution of (R)-21 (3.23 g, 17.37 mmol, 1 eq) in CH2Cl2 (75 mL) and MeOH (15 mL) at -78°C until the blue color of the solution persisted. Then O2 was bubbled for 10 min and PPh3 (5.47 g, 20.84 mmol, 1.2 eq) was added. The mixture was warmed to room temperature and stirred for 2 h. The solvents were removed in vacuo and the residue was purified by flash chromatography (Pen/Et2O 2:1) to afford alde- hyde 22 (2.91 g, 15.5 mmol, 89%) as a colorless liquid. General Data: C9H16O4; FW: 188.10;
Figure imgf000051_0003
= +30.08 (c = 1.25, CHCl3); TLC: Rf= 0.25 (Pentane/Et2O 2:1); UV (-); Vanillin: yellow. 1H-NMR (600 MHz, CDCl3): δ (ppm): 9.76 (s, 1H); 3.93-3.89 (m, 1H); 3.50 (s, 3H); 2.69 (dd, J = 16.06 Hz, J = 4.86 Hz, 1H); 2.60 (dd, J = 16.41 Hz, J = 6.68 Hz, 1H); 1.44 (s, 9H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 202.38; 169.14; 82.06; 81.62; 58.65; 36.99; 28.01. Example 21: tert-Butyl (R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynoate (24)
Figure imgf000051_0002
nBuLi 2.5 M in hexane (8 mL, 20.05 mmol, 1.3 eq) was added dropwise to a suspension of Phosphonium Bromide 23 (9.96 g, 18.5 mmol, 1.2 eq) in THF (100 mL) at -78°C. The red solution was stirred at 0°C for 30 min and then aldehyde 22 (2.9 g, 15.42 mmol, 1 eq) in THF (20 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 30 min. The re- action was quenched by addition of saturated NH4Cl aqueous solution (100 mL) and the layers were separated. The aqueous phase was extracted with Et2O (3x80 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by flash chro- matography (Pen/Et2O 40:1 to 30:1) gave E-24 (3.38 g, 9.25 mmol, 60%) and Z-24 (1.25 g, 3.42 mmol, 22%) E/Z 2.7:1. General Data: C21H38O3Si; FW: 366.26; = +8.2 (c = 0.5, CHCl3); TLC:
Figure imgf000052_0003
Rf= 0.45 (Pentane/Et2O 20:1); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl3): δ (ppm): 6.01 (dd, J = 15.86 Hz, J = 7.29 Hz, 1H); 5.76 (dd, J = 15.87 Hz, J = 1.05 Hz, 1H); 4.04-3.98 (m, 1H); 3.30 (s, 3H); 2.50 (dd, J = 14.53 Hz, J = 7.94 Hz, 1H); 2.37 (dd, J = 14.98 Hz, J = 5.67 Hz, 1H); 1.44 (s, 9H); 1.07 (s, 20H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 169.81; 142.32; 112.79; 104.44; 92.03; 80.86; 78.39; 56.98; 41.89; 28.06; 18.59; 11.24. Example 22: (R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynoic acid (25)
Figure imgf000052_0001
A solution of 24 (3.2 g, 8.74 mmol) in formic acid (13 mL) was stirred over- night at room temperature. The mixture was then concentrated in vacuo and azeotropically dried with toluene for 3 times to remove formic acid. Car- bossilic acid 25 was obtained (2.68 g, 8.65 mmol, 99%) as a slightly yellow liquid. General Data: C17H30O3Si; FW: 310.20; = +10.22 (c = 0.45, CHCl3);
Figure imgf000052_0002
TLC: Rf= 0.3 (Pentane/Et2O 5:1); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl3): δ (ppm): 6.02 (dd, J = 15.86 Hz, J = 7.29 Hz, 1H); 5.76 (dd, J = 15.87 Hz, J = 1.05 Hz, 1H); 4.04-3.98 (m, 1H); 3.30 (s, 3H); 2.50 (dd, J = 14.53 Hz, J = 7.94 Hz, 1H); 2.37 (dd, J = 14.98 Hz, J = 5.67 Hz, 1H); 1.07 (s, 20H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 175.91; 141.40; 113.50; 104.04; 92.69; 77.71; 57.03; 40.34; 18.60; 11.24. Example 23: methyl ((R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynoyl)-L-seri- nate (26)
Figure imgf000053_0001
DIPEA (3.5 mL, 20.1 mmol, 2.3 eq) and TFFH (2.54 g, 9.61 mmol, 1.1 eq) were added to a solution of carboxylic acid 26 (2.7 g, 8.74 mmol, 1 eq) in THF (30 mL) and the mixture was stirred for 2 h at room temperature. L-ser- ine methyl ester hydrochloride (1.63 g, 10.49 mmol, 1.2 eq) was added and the mixture was stirred for 3 h. Et2O (20mL) was added and the solution was washed with HCl 1 M (40 mL). The aqueous phase was extracted with Et2O (3x40 mL) and the organic layers were dried over Na2SO4, filtered and con- centrated in vacuo. Purification of the residue by flash chromatography (Et2O) afforded the serinate 26 (3.22 g, 7.82 mmol, 90%) as a yellow oil. General Data: C21H37NO5Si; FW: 411.24;
Figure imgf000053_0002
= +28.42 (c = 1.2, CHCl3); TLC: Rf= 0.25 (Et2O); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl3): δ (ppm): 7.32-7.29 (br, 1H); 6.01 (dd, J = 15.79 Hz, J = 7.33 Hz, 1H); 5.79 (d, J = 16.01 Hz, 1H); 4.71-4.61 (m, 1H); 4.09-4.00 (m, 1H); 3.99-3.89 (m, 1H); 3.79 (s, 3H); 3.35 (s, 3H); 2.55 (dd, J = 15.45 Hz, J = 8.28 Hz, 1H); 2.46 (dd, J = 14.90 Hz, J = 3.31 Hz, 1H); 1.07 (s, 20H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 170.79; 141.43; 113.26; 103.98; 92.85; 78.39; 63.24; 56.97; 54.87; 52.76; 41.98; 18.60; 11.23. Example 24: Methyl 2-((R,E)-2-methoxy-6-(triisopropylsilyl)hex-3-en-5-yn-1-yl)-4,5- dihydrooxazole-4-carboxylate (27)
Figure imgf000054_0001
DAST (1.13 mL, 8.56 mmol, 1.1 eq) was added dropwise to a solution of serinate 26 (3.2 g, 7.78 mmol, 1 eq) in CH2Cl2 (60 mL) at -78°C and the mix- ture was stirred for 2 h at -78°C. K2CO3 (2.15 g, 15.56 mmol, 2 eq) was added and the mixture was warmed to room temperature and stirred for 1 h. A saturated solution of NH4Cl (50 mL) was carefully added and, after the gas evolution ceased, the layers were separated. The aqueous phase was ex- tracted with CH2Cl2 (3x50 mL) and the combined organic extracts were washed with Brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product 27 as a yellow oil, which was used for the next step without further purification. General Data: C21H35NO4Si; FW: 393.23; = +58.59 (c = 0.85, CHCl3);
Figure imgf000054_0002
TLC: Rf= 0.4 (Et2O); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl3): δ (ppm): 6.03 (dd, J = 15.83 Hz, J = 7.39 Hz, 1H); 5.77 (dd, J = 16.01 Hz, J = 0.965 Hz, 1H); 4.76-4.72 (m, 1H); 4.50 (dd, J = 9.26 Hz, J = 8.02 Hz, 1H); 4.38 (dd, J = 11.18 Hz, J = 8.69 Hz, 1H); 4.07- 3.99 (m, 1H); 3.77 (s, 3H); 3.29 (s, 3H); 2.66 (dd, J = 14.63 Hz, J = 7.66 Hz, 1H); 2.49 (dd, J = 14.99 Hz, J = 5.87 Hz, 1H); 1.06 (s, 20H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 171.49; 167.42; 141.96; 113.14; 104.28; 92.31; 78.41; 69.40; 68.10; 56.95; 52.64; 34.30; 18.60; 11.24.
Example 25: Methyl (R,E)-2-(2-methoxy-6-(triisopropylsilyl)hex-3-en-5-yn-1- yl)oxazole-4-carboxylate (28)
Figure imgf000055_0001
The crude material 27 was dissolved in CH2Cl2 (60 mL), cooled to 0°C and protected from light with aluminium foil. DBU (2.24 mL, 15.56 mmol, 2 eq) and BrCCl3 (1.53 mL, 15.56 mmol, 2 eq) were sequentially added dropwise, then the bath was removed and the mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl solution (100 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3x100 mL) and the organic layers were dried over Na2SO4, fil- tered and concentrated in vacuo. Purification of the residue by flash chroma- tography (Pen/Et2O 2:1) afforded oxazole 28 (1.77 g, 4.51 mmol, 58% from 27) as a yellow oil. General Data: C21H33NO4Si; FW: 391.22; = -17.4 (c = 0.5, CHCl3); TLC:
Figure imgf000055_0002
Rf= 0.35 (Pentane/Et2O 2:1); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.16 (s, 1H); 6.04 (dd, J = 16.10 Hz, J = 7.51 Hz, 1H); 5.77 (dd, J = 15.93 Hz, J = 0.991 Hz, 1H); 4.18-4.11 (m, 1H); 3.90 (s, 3H); 3.26 (s, 3H); 3.08 (dd, J = 15.63 Hz, J = 8.13 Hz, 1H); 2.99 (dd, J = 15.05 Hz, J = 5.31 Hz, 1H); 1.07 (s, 20H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.47; 161.68; 143.99; 141.58; 133.35; 113.72; 103.98; 92.81; 79.14; 56.97; 52.16; 34.51; 18.59; 11.22.
Example 26: Methyl (R,E)-2-(2-methoxyhex-3-en-5-yn-1-yl)oxazole-4-carboxylate (29)
Figure imgf000056_0001
TBAF (1 M in THF, 4.6 mL, 4.6 mmol, 1.2 eq) was added dropwise at 0°C to a solution of TIPS oxazole 28 (1.5 g, 3.83 mmol, 1 eq) in THF (10 mL). The mixture was stirred for 1 h at room temperature and then quenched with wa- ter. The aqueous phase was extracted with Et2O and the organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the res- idue by flash chromatography (Pen/Et2O 2:1 to 1:1) afforded oxazole 29 (675 mg, 2.87 mmol, 75%) as a yellow oil. General Data: C12H13NO4; FW: 235.08; = -26.89 (c = 0.45, CHCl3
Figure imgf000056_0002
); TLC: Rf= 0.30 (Pentane/Et2O 1:1); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.16 (s, 1H); 6.10 (ddd, J = 16.19 Hz, J = 7.42 Hz, J = 0.434 Hz, 1H); 5.70 (ddd, J = 16.01 Hz, J = 2.15 Hz, J = 0.908 Hz, 1H); 4.19-4.12 (m, 1H); 3.89 (s, 3H); 3.26 (s, 3H); 3.08 (dd, J = 14.47 Hz, J = 7.89 Hz, 1H); 2.98 (dd, J = 14.74 Hz, J = 5.79 Hz, 1H); 2.92 (d, J = 2.30 Hz, 1H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.24; 161.59; 144.00; 142.99; 133.34; 112.29; 80.80; 78.91; 78.89; 56.95; 52.13; 34.35.
Example 27: (R,E)-2-(2-methoxyhex-3-en-5-yn-1-yl)oxazole-4-carboxylic acid (30)
Figure imgf000057_0001
LiOH (1 M in H2O, 3.9 mL, 3.9 mmol, 2.5 eq) was added to a solution of the oxazole 29 (367 mg, 1.56 mmol, 1 eq) in THF (1 mL) at room temperature. The mixture was stirred for 2 h and then quenched with 1 M HCl. The aque- ous phase was extracted with Et2O and the organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the acid 30 (326 mg, 1.54 mmol, 99%) as a yellow solid. General Data: C11H11NO4; FW: 221.07;
Figure imgf000057_0002
= -26.4 (c = 0.5, CHCl3); UV (+); Vanillin: brown. 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.25 (s, 1H); 6.13 (ddd, J = 15.97 Hz, J = 7.36 Hz, J = 0.566 Hz, 1H); 5.73 (ddd, J = 16.02 Hz, J = 2.38 Hz, J = 0.977 Hz, 1H); 4.23-4.15 (m, 1H); 3.27 (s, 3H); 3.14 (dd, J = 15.14 Hz, J = 7.66 Hz, 1H); 3.05 (dd, J = 15.02 Hz, J = 5.57 Hz, 1H); 2.93 (d, J = 3.31 Hz, 1H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 164.80; 162.73; 145.01; 142.88; 132.94; 112.43; 80.81; 78.96; 78.90; 56.98; 52.13; 34.22.
Example 28: Methyl 2-((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2-methoxy-12-(methox- ymethoxy)-11,11-dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4- carboxylate (30)
Figure imgf000058_0001
The vinyl iodide 18 (300 mg, 0.847 mmol, 1 eq) was dissolved in degassed CH3CN (5 mL) and CuI (39 mg, 0.254 mmol, 0.3 eq) and PdCl2(PPh3)2 (60 mg, 0.0847 mmol, 0.1 eq) were added. The mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -20°C. NEt3 (0.706 mL, 5.08 mmol, 6 eq) was added, followed by a slow addition of the enyne 29 (240 mg, 1.02 mmol, 1.2 eq) in degassed CH3CN (3 mL). The solution became red and af- ter 15 min the bath was removed. The mixture was stirred for 1 h at room temperature and quenched with NH4Cl solution. The aqueous phase was ex- tracted with Et2O and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chroma- tography (Et2O/Pen 2:1) to give the monomer 31 (360 mg, 0.781 mmol, 92 %) as a yellow oil. General Data: C25H35NO7; FW: 461.24; TLC: Rf= 0.25 (Et2O/Pentane 2:1); UV (+); Vanillin: black. 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.16 (s, 1H); 6.19-6.08 (m, 1H); 5.96 (dd, J = 8.56 Hz, J = 7.30 Hz, 1H); 5.82 (dd, J = 15.9 Hz, J = 2.07 Hz, 1H); 5.73-5.61 (m, 2H); 5.33 (qd, J = 6.42 Hz, J = 1.71 Hz, 1H); 4.71 (d, J = 6.67 Hz, 1H); 4.46 (d, J = 6.67 Hz, 1H); 4.16 (q, J = 7.48 Hz, 1H); 3.90 (s, 3H); 3.89 (app dd, J = 8.46 Hz, J = 4.55 Hz, 1H); 3.62 (dd, J = 10.16, J = 2.80, 1H); 3.37 (s, 3H); 3.26 (s, 3H); 3.10 (dd, J = 7.75 Hz, J = 6.97 Hz, 1H); 2.99 (dd, J = 9.30 Hz, J = 5.62 Hz, 1H); 2.61-2.50 (m, 1H); 1.65 (s, 1H); 2.48-2.32 (m, 1H); 1.74 (dd, J = 6.50 Hz, J = 1.70 Hz, 3H); 0.976 (s, 3H); 0.809 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.41; 161.63; 143.99; 142.54; 140.27; 133.33; 132.38; 126.93; 113.78; 110.11; 93.04; 91.10; 88.02; 84.69; 79.22; 77.87; 56.83; 55.99; 52.15; 41.08; 34.55; 32.88; 21.39; 17.87; 16.02. Example 29: (2E,4S,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)oxazol-2-yl)- 4-(methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn-6-yl 2- ((R,E)-2-methoxyhex-3-en-5-yn-1-yl)oxazole-4-carboxylate (32)
Figure imgf000059_0001
The monomer 31 (320 mg, 0.694 mmol, 1 eq) and the acid 30 (291 mg, 1.32 mmol, 1.5 eq) and DMAP (85 mg, 0.694 mmol, 1 eq) were dissolved in CH2Cl2 (10 mL) and cooled to 0°C. DCC (716 mg, 3.47 mmol, 5 eq) was added and the mixture was stirred overnight at room temperature. The solu- tion was directly chromatographed (CH2Cl2/MeOH 99:1) to afford ester 32 (460 mg, 0.692 mmol, 99%) as a yellow wax, containing DCU impurity. General Data: C36H44N2O10; FW: 664.30;
Figure imgf000059_0002
= +23.16 (c = 0.6, CHCl3); TLC: Rf= 0.25 (CH2Cl2/MeOH 99:1); UV (+); Vanillin: black. 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.17 (s, 1H); 8.06 (s, 1H); 6.13 (dd, J = 16.38 Hz, J = 7.39 Hz, 1H); 5.98 (dd, J = 15.5 Hz, J = 7.39 Hz, 1H); 5.98- 5.92 (m, 1H); 5.87 (dd, J = 15.92 Hz, J = 2.03 Hz, 1H); 5.73 (ddd, J = 16.25 Hz, J = 2.33 Hz, J = 1.09 Hz, 1H); 5.63-5.53 (m, 2H); 5.34 (app dd, J = 9.86 Hz, J = 3.28 Hz, 1H); 5.31 (app qd, J = 7.63 Hz, J = 1.74 Hz, 1H); 4.68 (d, J = 6.78 Hz, 1H); 4.45 (d, J = 6.68 Hz, 1H); 4.18 (q, J = 6.06 Hz, 2H); 3.90 (s, 3H); 3.82 (d, J = 8.69 Hz, 1H); 3.62 (dd, J = 10.16 Hz, J = 2.80 Hz, 1H); 3.37 (s, 3H); 3.28 (s, 6H); 3.14-3.05 (m, 2H); 3.03-2.96 (m, 2H); 2.92 (d, J = 2.15 Hz, 1H); 2.79-2.64 (m, 2H); 1.72 (dd, J = 6.59 Hz, J = 1.46 Hz, 3H); 1.02 (s, 3H); 0.948 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.37; 162.25; 161.63; 160.62; 144.03; 143.53; 143.13; 140.49; 140.40; 133.45; 133.38; 132.19; 126.76; 113.61; 112.20; 111.11; 93.35; 91.26; 87.96; 81.37; 80.91; 79.20; 78.87; 78.83; 56.98; 55.75; 52.14; 41.61; 34.55; 34.37; 31.08; 25.45; 19.93; 19.46; 17.92. Example 30: (2E,4S,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)oxazol-2-yl)- 4-(methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn-6-yl 2- ((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2-methoxy-12-(methoxymethoxy)- 11,11-dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4-carboxylate (33)
Figure imgf000060_0001
The vinyl iodide 18 (120 mg, 0.339 mmol, 1 eq) was dissolved in degassed CH3CN (5 mL) and CuI (15 mg, 0.102 mmol, 0.3 eq) and PdCl2(PPh3)2 (24 mg, 0.0339 mmol, 0.1 eq) were added. The mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -20°C. NEt3 (0.283 mL, 2.03 mmol, 6 eq) was added, followed by a slow addition of the enyne 32 (300 mg, 0.452 mmol, 1.33 eq) in degassed CH3CN (3 mL). The solution became red and af- ter 30 min the bath was removed. The mixture was stirred for 1 h at room temperature and quenched with NH4Cl solution. The aqueous phase was ex- tracted with Et2O and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chroma- tography (CH2Cl2/MeOH 99:1) to give 33 (246 mg, 0.276 mmol, 82%) as a yellow oil. General Data: C49H66N2O13; FW: 890.46;
Figure imgf000061_0001
= -22.83 (c = 0.6, CHCl3); TLC: Rf= 0.20 (CH2Cl2/MeOH 99:1); UV (+); Vanillin: black. 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.17 (s, 1H); 8.05 (s, 1H); 6.19-6.09 (m, 1H); 6.03-5.83 (m, 5H); 5.70-5.51 (m, 4H); 5.37-5.25 (m, 3H); 4.70 (dd, J = 15.62 Hz, J = 6.57 Hz, 1H); 4.45 (t, J = 6.86 Hz, 1H); 4.22-4.13 (m, 2H); 3.90 (s, 3H); 3.89 (d, J = 9.06 Hz, 1H); 3.82 (d, J = 8.55 Hz, 1H); 3.56 (dt, J = 10.20 Hz, J = 3.26 Hz, 1H); 3.37 (s, 6H); 3.28 (s, 3H); 3.27 (s, 3H); 3.15-2.96 (m, 4H); 2.78-2.64 (m, 2H); 2.61-2.49 (m, 1H); 2.47-2.32 (m, 1H); 1.74 (dd, J = 6.43 Hz, J = 1.58 Hz, 3H); 1.72 (dd, J = 6.49 Hz, J = 1.40 Hz, 3H); 1.02 (s, 3H); 0.977 (s, 3H); 0.944 (s, 3H); 0.813 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.45; 162.37; 161.62; 160.63; 144.03; 143.51; 142.52; 140.49; 140.42; 133.41; 133.36; 132.39; 132.19; 126.93; 126.76; 125.51; 113.67; 113.61; 111.09; 110.13; 93.34; 93.05; 91.27; 91.16; 87.99; 87.96; 84.71; 81.36; 79.20; 77.85; 77.23; 56.87; 56.85; 56.01; 52.15; 41.63; 41.07; 34.50; 34.39; 32.87; 31.13; 21.41; 19.88; 19.36; 17.93; 17.86; 16.02. Example 31: 2-((2R,3E,7Z,10S,12S,13E)-10-((2-((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2- methoxy-12-(methoxymethoxy)-11,11-dimethylpentadeca-3,7,13-trien-5-
yn-1-yl)oxazole-4-carbonyl)oxy)-2-methoxy-12-(methoxymethoxy)-11,11- dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4-carboxylic acid (34)
Figure imgf000062_0001
33 (48 mg, 0.0539 mmol, 1 eq) was dissolved in THF (1 mL) and treated at room temperature with LiOH (1 M in H2O, 0.108 mL, 0.108 mmol, 2 eq). The mixture was stirred overnight at room temperature and neutralized with 1 M HCl. The aqueous phase was extracted with Et2O and the organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give seco-acid 34 (44 mg, 0.0502 mmol, 93%) as a yellow wax, which was used without fur- ther purification. General Data: C48H64N2O13; FW: 876.44; = -26.4 (c = 0.5, CHCl3); UV (+); Vanillin: grey.
Figure imgf000062_0002
1H-NMR (600 MHz, CDCl3): δ (ppm): 8.20 (s, 1H); 8.10 (s, 1H); 6.18-6.09 (m, 1H); 6.04-5.80 (m, 5H); 5.73-5.52 (m, 4H); 5.38-5.26 (m, 3H); 4.71 (dd, J = 13.08 Hz, J = 6.64 Hz, 1H); 4.46 (dd, J = 7.04 Hz, J = 4.02 Hz, 1H); 4.24- 4.13 (m, 2H); 3.90 (d, J = 9.19 Hz, 1H); 3.83 (d, J = 8.68 Hz, 1H); 3.64 (dd, J = 10.12 Hz, J = 2.74 Hz, 1H); 3.39 (s, 3H); 3.38 (s, 3H); 3.30 (s, 3H); 3.28 (s, 3H); 3.18-2.94 (m, 4H); 2.82-2.51 (m, 3H); 2.47-2.33 (m, 1H); 1.74 (dd, J = 6.48 Hz, J = 1.52 Hz, 3H); 1.71 (dd, J = 6.38 Hz, J = 1.16 Hz, 3H); 1.03 (s, 3H); 0.983 (s, 3H); 0.950 (s, 3H); 0.815 (s, 3H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.42; 162.36; 162.10; 160.61; 144.36; 143.74; 142.44; 140.44; 140.35; 133.46; 133.34; 132.47; 132.22; 126.86; 126.70; 125.51; 113.72; 113.64; 111.25; 110.20; 93.39; 93.03; 91.24; 91.20; 88.00; 87.92; 84.77; 81.54; 79.14; 77.98; 77.22; 56.85; 56.02; 55.99; 49.54; 41.63; 41.07; 34.59; 34.54; 33.94; 31.06; 21.39; 19.92; 19.45; 17.93; 17.86; 16.02. Example 32: (16,16’)-Bis(methoxymethyl)-(9,10,9’,10’)-tetradehydridodisorazole C1 (35)
Figure imgf000063_0001
The crude seco-acid 34 (28 mg, 0.0319 mmol, 1 eq) was dissolved in THF (2.5 mL) and NEt3 (89 µL, 0.638 mmol, 20 eq) and TCBC (50 µL, 0.319 mmol, 10 eq) were added at room temperature. The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (1.5 mL) and added dropwise to a solution of DMAP (156 mg, 1.28 mmol, 40 eq) in toluene (45 mL). The mixture was stirred overnight at room temperature and then quenched with NH4Cl solution (10 mL) and water (10 mL) and the aqueous phase was extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH 99:1) to afford the macrocycle 35 (22 mg, 0.0255, 80%) as a colorless wax. General Data: C48H62N2O12; FW: 858.43; UV (+); TLC: Rf= 0.55 (CH2Cl2/MeOH 50:1 Vanillin: black. 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.04 (s, 2H); 6.03-5.88 (m, 4H); 5.70- 5.47 (m, 6H); 5.44-5.23 (m, 4H); 4.69 (d, J = 7.18 Hz, 1H); 4.45 (d, J = 6.68 Hz, 1H); 4.17-3.99 (m, 2H); 3.81 (d, J = 9.36 Hz, 2H); 3.38 (s, 6H); 3.36 (s, 6H); 3.32-3.25 (m, 2H); 3.07-2.83 (m, 4H); 2.53-2.43 (m, 2H); 1.73 (dd, J = 6.48 Hz, J = 1.52 Hz, 6H); 1.71 (dd, J = 6.36 Hz, J = 1.27 Hz, 3H); 1.03 (s, 6H); 0.962 (s, 6H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 161.64; 160.52; 144.36; 143.33; 141.14; 140.31; 133.60; 132.38; 126.65; 125.51; 113.51; 112.08; 93.37; 90.80; 87.75; 81.47; 79.56; 77.22; 56.85; 56.07; 41.43; 33.96; 25.59; 19.84; 19.29; 17.94. Example 33: (16,16’)-Bis(methoxymethyl)-disorazole C1 (36)
Figure imgf000064_0001
Nitrogen is bubbled for 15 min through a suspension of Zinc (3 g, 45.88 mmol) in H2O (18 mL) and then Cu(OAc)2·H2O (300 mg, 1.50 mmol) was added at room temperature and after 15 min AgNO3 (300 mg, 1.77 mmol) was added (exothermic reaction). The mixture was stirred for 30 min at room temperature, filtered by suction and washed with H2O (30 mL), MeOH (20 mL), acetone (20 mL) and Et2O (20 mL). This activated zinc solids were added to a solution of 35 (20 mg, 0.0233 mmol) in MeOH/H2O 1:1 (5 mL). The mixture was stirred overnight at 50°C and then filtered on a pad of silica and washed with MeOH. The filtrate was concentrated in vacuo and the resi- due was purified by flash chromatography (CH2Cl2/MeOH 60:1) to afford 36 (12 mg, 0.0139, 60%) as a colorless oil. General Data: C48H66N2O12; FW: 862.46; UV (+); TLC: Rf= 0.40 (CH2Cl2/MeOH 50:1) Vanillin: dark blue. 1H-NMR (600 MHz, CDCl3): δ (ppm): 7.89 (s, 2H); 6.44 (dd, J = 14.93 Hz, J = 11.38 Hz, 2H); 6.34 (t, J = 11.38 Hz, 2H); 6.21 (t, J = 11.64 Hz, 2H); 5.90 (t, J = 11.04 Hz, 2H); 5.63-5.58 (m, 2H); 5.56-5.51 (m, 2H); 5.38 (dd, J = 10.91 Hz, J = 2.48 Hz, 1H); 5.34-5.27 (m, 4H); 4.68 (d, J = 6.67 Hz, 1H); 4.43 (d, J = 6.67 Hz, 1H); 4.15-4.10 (m, 2H); 3.81 (d, J = 8.73 Hz, 2H); 3.36 (s, 6H); 3.26 (s, 6H); 3.12 (dd, J = 14.66 Hz, J = 6.03 Hz, 2H); 2.97-2.86 (m, 2H); 2.78 (dd, J = 14.83 Hz, J = 7.27 Hz, 2H); 2.63-2.50 (m, 2H); 1.73 (dd, J = 6.48 Hz, J = 1.52 Hz, 6H); 1.73 (dd, J = 6.59 Hz, J = 1.22 Hz, 3H); 0.984 (s, 6H); 0.919 (s, 6H). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.23; 160.59; 143.20; 133.34; 133.03; 132.28; 130.13; 128.98; 127.95; 126.73; 125.59; 125.55; 93.26; 81.30; 79.79; 56.55; 56.13; 41.44; 35.06; 29.70; 19.95; 19.45; 17.94. Example 34: Disorazole C1 (37)
Figure imgf000065_0001
MOM protected disorazole C136 (1 mg, 1.16 µmol) was dissolved in MeOH (0.3 mL) and cooled to 0°C. HCl 6 M (0.6 mL) was added dropwise and then the mixture was stirred for 4 days at 0°C. The reaction was quenched with saturated aqueous NaHCO3 solution and the aqueous phase was extracted with Et2O. The organic extracts were dried over MgSO4, filtered and concen- trated in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH 50:1) to give Disorazole C137(0.6 mg, 0.7 µmol, 60%) as a colorless wax. General Data: C44H58N2O10; FW: 774.41; UV (+); TLC: Rf= 0.20 (CH2Cl2/MeOH 50:1) Vanillin: dark blue. 1H-NMR (600 MHz, CD3OD): δ (ppm): δ 8.23 (s, 2 H); 6.50 (dd, J = 15.2 Hz, J = 11.5 Hz, 2H); 6.40 (app t, J = 11.2 Hz, 2 H); 6.28 (dd, 2 H, J = 11.4 Hz, J = 11.1 Hz, 2 H); 5.91 (dd, J = 11.2 Hz, J = 10.9 Hz, 2 H); 5.66 (dq, J = 15.2 Hz, J = 6.6 Hz, 2 H); 5.57 (ddd, J = 15.2 Hz, J = 7.8 Hz, J = 1.4 Hz, 2H); 5.54 (dd, J = 15.0 Hz, J = 8.3 Hz, 2 H); 5.48 (app dt, J = 10.0 Hz, J = 6.7 Hz, 2 H); 5.25 (dd, J = 11.3 Hz, J = 2.2 Hz, 2 H); 4.13 (ddd, J = 7.8 Hz, 7.2 Hz, 5.5 Hz, 2 H); 3.84 (d, 2 H, J = 7.8 Hz); 3.21 (s, 6 H), 2.99 (dd, 2 H, J = 15.5, J = 7.4 Hz); 2.76 (dd, J = 15.5 Hz, J = 5.4 Hz, 2 H); 2.69 (ddd, J = 13.8 Hz, J = 10.9 Hz, J = 10.2 Hz, 2 H); 2.38 (dd, J = 13.8 Hz, J = 6.1 Hz, 2 H); 1.69 (dd, J = 6.4 Hz, J = 1.3 Hz, 6 H); 1.00 (s, 6 H); 0.95 (s, 6 H). 13C-NMR (151 MHz, CD3OD) δ 164.12; 162.26; 145.83; 134.15; 134.09; 131.68; 130.88; 129.96; 129.63; 129.30; 127.36; 126.79; 80.57; 78.75; 77.84; 56.83; 42.70; 35.97; 29.24; 19.41; 19.32; 18.03. Example 35: Methyl 2-((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)- 11,11-dimethyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)ox- azole-4-carboxylate (40)
Figure imgf000066_0001
The vinyl iodide 17 (397 mg, 0.847 mmol, 1 eq) was dissolved in degassed CH3CN (5 mL) and CuI (39 mg, 0.254 mmol, 0.3 eq) and PdCl2(PPh3)2 (60 mg, 0.0847 mmol, 0.1 eq) were added. The mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -15°C (ice/acetone bath). NEt3 (0.706 mL, 5.08 mmol, 6 eq) was added, followed by a slow addition of the enyne 29 (240 mg, 1.02 mmol, 1.2 eq) in degassed CH3CN (3 mL). The solution became red and after 15 min the bath was removed. The mixture was stirred for 1 h at room temperature and quenched with saturated aqueous NH4Cl solution (10 mL). The aqueous phase was extracted with Et2O (3x10 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (pentane/Et2O 2:1) to give the monomer 40 (414 mg, 0.720 mmol, 85%) as a yellow oil. General Data: C31H49NO7Si; FW: 575.33; TLC: Rf= 0.20 (pentane/Et2O 2:1); UV (+); Vanillin: black;
Figure imgf000066_0002
= -28.4 (c = 0.5, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.16 (s, 1H, NC=CH); 6.10-6.02 (m, 1H, CH2CH=CH); 5.99 (dd, J = 15.9, 7.5 Hz, 1H, CCH=CHCH); 5.89 (dd, J = 15.9, 2.2 Hz, 1H, CCH=CHCH2); 5.66- 5.54 (m, 2H, CH(OCH3)CH=CH, CH=CHCH3); 5.37-5.28 (m, 1H, CH=CHCH3); 4.66 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.46 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.21-4.13 (m, 1H, CHOCH3); 3.90 (s, 3H, COOCH3); 3.84 (d, J = 9.3 Hz, 1H, CH2CHOTES); 3.67 (dd, J = 7.1, 3.8 Hz, 1H, CH2CHOTES); 3.35 (s, 3H, CHOCH3); 3.27 (s, 3H, CHOCH2OCH3); 3.10 (dd, J = 12.6, 5.6 Hz, 1H, 1CH2CHOCH3); 2.99 (dd, J = 15.0, 5.5 Hz, 1H, 1CH2CHOCH3); 2.62-2.53 (m, 1H, 1CH2CH=CH); 2.45-2.37 (m, 1H, 1CH2CH=CH); 1.71 (dd, J = 6.4, 1.6 Hz, 3H, CH=CHCH3); 0.952 (app t, J = 8.0 Hz, 9H, OSi(CH2CH3)3); 0.922 (s, 3H, CCH3); 0.849 (s, 3H, CCH3); 0.599 (q, J = 8.0 Hz, 6H, OSi(CH2CH3)3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.6 (C=O); 161.8 (C=N); 144.1 (CH); 143.2 (CH); 140.4 (CH); 133.5 (C); 131.0 (CH); 128.0 (CH); 113.9 (CH); 109.5 (CH); 93.6 (CH2); 91.2 (C); 88.5 (C); 81.6 (CH); 79.4 (CH); 76.5 (CH); 56.9 (CH3); 55.7 (CH3); 52.3 (CH3); 43.1 (C); 34.7 (CH2); 34.5 (CH2); 19.8 (CH3); 19.4 (CH3); 18.0 (CH3); 7.3 (CH3); 5.7 (CH2). IR(neat): 3656 (w); 2980 (s); 2884 (m); 1749 (m); 1585 (m); 1461 (m); 1382 (m); 1238 (m); 1142 (m); 1091 (s); 1036 (s); 1004 (s); 956 (s); 923 (m); 727 (s); 678 (m); 604 (w) cm-1. MS (ESI): m/z (%): 418.20 (100), 514.29 (81), 598.31 (22), 593.36 (18) [M+NH4]+, 350.17 (8), 482.27 (6), 576.33 (<1) [M+H]+. HRMS (ESI) m/z: [M+H]+ Calcd for C31H50NO7Si: 576.3357; found: 576.3363. Example 36: Methyl-2-((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2-methoxy-12-(methox- ymethoxy)-11,11-dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4- carboxylate (31)
Figure imgf000067_0001
CSA (10 mg, 0.0444 mmol, 0.2 eq) was added at 0°C to a solution of TES protected monomer 40 (128 mg, 0.222 mmol, 1 eq) in CH2Cl2 (6 mL) and MeOH (6 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Saturated aqueous NaHCO3 solution (15 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3x10 mL) and the combined organic extracts were dried over Na2SO4, fil- tered and concentrated in vacuo. The residue was purified by flash chroma- tography (Et2O/pentane 2:1) giving deprotected monomer 31 (97 mg, 0.210 mmol, 95%) as a slightly yellow oil. General Data: C25H35NO7; FW: 461.24; TLC: Rf= 0.25 (Et2O/Pentane 2:1); UV (+); Vanillin: black; [
Figure imgf000068_0001
= -36.11 (c = 1.75, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.16 (s, 1H, NC=CH); 6.24-6.15 (m, 1H, CH2CH=CH); 5.96 (dd, J = 15.8, 7.5 Hz, 1H, CCH=CHCH); 5.87 (d, J = 15.9 Hz, 1H, CCH=CHCH2); 5.71-5.61 (m, 2H, CH(OCH3)CH=CH, CH=CHCH3); 5.43-5.36 (m, 1H, CH=CHCH3); 4.65 (d, J = 6.5 Hz, 1H, 1OCH2OCH3); 4.47 (d, J = 6.5 Hz, 1H, 1OCH2OCH3); 4.21-4.12 (m, 1H, CHOCH3); 3.90 (s, 3H, COOCH3); 3.89 (1H, CH2CHOH); 3.68 (d, J = 10.0 Hz, 1H, CHOCH2OCH3); 3.38 (s, 3H, CHOCH3); 3.26 (s, 3H, CHOCH2OCH3); 3.09 (dd, J = 15.1, 7.9 Hz, 1H, 1CH2CHOCH3); 2.99 (dd, J = 14.9, 5.3 Hz, 1H, 1CH2CHOCH3); 2.54 (dd, J = 14.3, 7.6 Hz, 1H, 1CH2CH=CH); 2.37- 2.28 (m, 1H, 1CH2CH=CH); 1.75 (d, J = 6.3 Hz, 3H, CH=CHCH3); 0.917 (s, 3H, CCH3); 0.867 (s, 3H, CCH3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.6 (C=O); 161.8 (C=N); 144.1 (CH); 143.3 (CH); 140.3 (CH); 133.5 (C); 132.0 (CH); 126.9 (CH); 114.0 (CH); 109.8 (CH); 93.8 (CH2); 91.1 (C); 88.3 (C); 84.7 (CH); 79.4 (CH); 76.1 (CH); 56.9 (CH3); 56.2 (CH3); 52.3 (CH3); 41.0 (C); 34.7 (CH2); 32.8 (CH2); 21.1 (CH3); 17.7 (CH3); 18.0 (CH3). IR(neat): 3483 (br); 3164 (w); 2934 (m); 2826 (w); 2249 (w); 1734 (m); 1585 (m); 1438 (m); 1322 (m); 1166 (m); 1101 (s); 1030 (s); 927 (m); 917 (m); 731 (s) cm-1. MS (ESI): m/z (%): 304.11 (100), 400.21 (48), 479.27 (20) [M+NH4]+, 272.09 (19), 430.22 (15), 462.24 (12) [M+H]+, 209.13 (3). HRMS (ESI) m/z: [M+H]+ Calcd for C25H36NO7: 462.2492; found: 462.2473. Example 37: 2-((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)-11,11-di- methyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4- carboxylic acid (42)
Figure imgf000069_0001
40 (150 mg, 0.261 mmol, 1 eq) was dissolved in THF (5 mL) and treated at room temperature with LiOH (1 M in H2O, 0.783 mL, 0.783 mmol, 3 eq). The mixture was stirred for 3 h at room temperature and neutralized with 1 M HCl (2 mL). The aqueous phase was extracted with Et2O (3x3 mL) and the or- ganic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give acid 42 (146 mg, 0.259 mmol, 99%) as a yellow oil, which was used for the next step without further purification. General Data: C30H47NO7Si; FW: 561.31; TLC: UV (+); Vanillin: black; = -36.9 (c = 1.0, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.24 (s, 1H, NC=CH); 6.09-6.02 (m, 1H, CH2CH=CH); 6.00 (dd, J = 15.6, 7.5 Hz, 1H, CCH=CHCH); 5.89 (d, J = 15.9 Hz, 1H, CCH=CHCH2); 5.69-5.55 (m, 2H, CH(OCH3)CH=CH, CH=CHCH3); 5.37-5.28 (m, 1H, CH=CHCH3); 4.68 (d, J = 6.4 Hz, 1H,1OCH2OCH3); 4.48 (d, J = 6.4 Hz, 1H, 1OCH2OCH3); 4.23-4.13 (m, 1H, CHOCH3); 3.84 (d, J = 9.0 Hz, 1H, CHOCH2OCH3); 3.65 (dd, J = 6.8, 3.5 Hz, 1H, CHOTES); 3.36 (s, 3H, CHOCH3); 3.28 (s, 3H, CHOCH2OCH3); 3.13 (dd, J = 15.0, 7.4 Hz, 1H, 1CH2CHOCH3); 3.03 (dd, J = 15.0, 4.2 Hz, 1H, 1CH2CHOCH3); 2.59-2.51 (m, 1H, 1CH2CH=CH); 2.45-2.36 (m, 1H, 1CH2CH=CH); 1.72 (d, J = 5.9, Hz, 3H, CH=CHCH3); 0.951 (t, J = 7.8 Hz, 9H, OSi(CH2CH3)3); 0.925 (s, 3H, CCH3); 0.853 (s, 3H, CCH3); 0.598 (q, J = 7.9 Hz, 6H, OSi(CH2CH3)3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 164.4 (C=O); 162.8 (C=N); 145.0 (CH); 143.2 (CH); 140.2 (CH); 133.0 (C); 131.1 (CH); 127.9 (CH); 114.0 (CH); 109.5 (CH); 93.6 (CH2); 91.2 (C); 88.5 (C); 81.8 (CH); 79.3 (CH); 76.5 (CH); 56.9 (CH3); 55.7 (CH3); 43.2 (C); 34.4 (CH2); 30.5 (CH2); 19.8 (CH3); 19.4 (CH3); 18.0 (CH3); 7.3 (CH3); 5.7 (CH2). IR(neat): 2953 (m); 2912 (m); 2877 (m); 1716 (m); 1587 (m); 1440 (m); 1359 (w); 1234 (w); 1144 (m); 1090 (s); 1036 (s); 957 (m); 921 (m); 826 (m); 726 (s); 542 (w) cm-1. MS (ESI): m/z (%): 404.18 (100), 579.34 (78) [M+NH4]+, 500.28 (51), 372.16 (27), 468.25 (10), 336.15 (8), 562.32 (3) [M+H]+. HRMS (ESI) m/z: [M+H]+ Calcd for C30H48NO7Si: 562.3200; found: 562.3188. Example 38: (2E,4S,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)oxazol-2-yl)- 4- (methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn-6-yl 2- ((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)-11,11-dime- thyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4-car- boxylate (43)
Figure imgf000070_0001
The crude acid 42 (91 mg, 0.162 mmol, 1.5 eq) was dissolved in THF (5 mL) and treated at room temperature with NEt3 (90 µL, 0.648 mmol, 6 eq) and 2,4,6-trichlorobenzoyl chloride (68 µL, 0.432 mmol, 4 eq). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added dropwise to a solution of alcohol 31 (50 mg, 0.108 mmol, 1 eq) and DMAP (79 mg, 0.648 mmol, 6 eq) in toluene (5 mL). The mixture was stirred overnight at room temperature and then quenched with saturated aqueous NH4Cl solution (15 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The organic layers were dried over Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 2:1 to 1:1) to afford the dimer 43 (81 mg, 0.0813 mmol, 75%) as a slightly yellow oil. General Data: C55H80N2O13Si; FW: 1004.54; TLC: Rf = 0.30 (Et2O/pentane 2:1); UV (+); Vanillin: black; = +29.65 (c = 1.75, CHCl3
Figure imgf000071_0001
). 1H-NMR (400 MHz, CDCl3): δ (ppm): 8.18 (s, 1H, NC=CH); 8.06 (s, 1H, NC=CH); 6.10-5.94 (m, 4H, CH=CH); 5.93-5.84 (m, 2H, CH=CH); 5.70-5.52 (m, 4H, CH=CH); 5.42-5.28 (m, 2H, CH=CH); 5.25 (app dd, J = 7.6, 5.5 Hz, 1H, CHOC=O); 4.65 (dd, J = 6.5, 3.0 Hz, 2H, OCH2OCH3); 4.46 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.39 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.23-4.13 (m, 2H, CHOCH3); 3.90 (s, 3H, COOCH3); 3.84 (d, J = 9.0 Hz, 1H, CHOCH2OCH3); 3.76 (d, J = 9.0 Hz, 1H, CHOCH2OCH3); 3.66 (dd, J = 7.0, 3.8 Hz, 1H, CH2CHOTES); 3.34 (s, 3H, CHOCH3); 3.32 (s, 3H, CHOCH3); 3.28 (s, 3H, CHOCH2OCH3); 3.27 (s, 3H, CHOCH2OCH3); 3.15-2.93 (m, 4H, CH2CHOCH3); 2.72-2.62 (m, 2H, CH2CH=CH); 2.60-2.51 (m, 1H, 1CH2CH=CH); 2.46-2.36 (m, 1H, 1CH2CH=CH); 1.71 (dt, J = 6.4, 1.5 Hz, 6H, CH=CHCH3); 1.03 (s, 3H, CCH3); 0.966 (s, 3H, CCH3); 0.945 (app t, J = 7.9 Hz, 9H, OSi(CH2CH3)3); 0.918 (s, 3H, CCH3); 0.844 (s, 3H, CCH3); 0.591 (q, J = 8.0 Hz, 6H, OSi(CH2CH3)3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 162.6 (C=O); 162.5 (C=O); 161.8 (C=N); 160.8 (C=N); 144.2 (CH); 143.6 (CH); 143.2 (CH); 140.6 (CH); 140.5 (CH); 133.6 (C); 133.5 (C); 132.1 (CH); 131.0 (CH); 128.0 (CH); 127.1 (CH); 125.6 (CH); 113.8 (CH); 113.7 (CH); 111.1 (CH); 109.5 (CH); 93.6 (CH2); 93.6 (CH2); 91.4 (C); 91.2 (C); 88.4 (C); 88.0 (C); 81.6 (CH); 81.6 (CH); 79.3 (CH); 77.4 (CH); 77.0 (CH); 76.4 (CH); 57.0 (CH3); 56.9 (CH3); 56.1 (CH3); 55.7 (CH3); 52.3 (CH3); 43.2 (C); 41.8 (C); 34.7 (CH2); 34.5 (CH2); 31.4 (CH2); 30.4 (CH2); 19.9 (CH3); 19.8 (CH3); 19.5 (CH3); 19.4 (CH3); 18.1 (CH3); 18.0 (CH3); 7.3 (CH3); 5.7 (CH2). IR(neat): 2953 (m); 2879 (m); 2284 (w); 1737 (m); 1583 (m); 1439 (m); 1318 (m); 1168 (m); 1099 (s); 1033 (s); 911 (s); 807 (m); 728 (s); 647 (m); 551 (w) cm-1. MS (ESI): m/z (%): 1005.55 (100) [M+H]+, 1022.56 (760) [M+NH4]+, 943.52 (45), 973.53 (28), 847.43 (8). HRMS (ESI) m/z: [M+H]+ Calcd for C55H81N2O13Si: 1005.5508; found: 1005.5594 Example 39: (16,16’)-Bis(methoxymethyl)-(9,10,9’,10’)-tetradehydridodisorazole C1 (35) CSA (3 mg, 0.0132 mmol, 0.2 eq) was added at 0°C to a solution TES pro- tected dimer 43 (67 mg, 0.0661 mmol, 1 eq) in CH2Cl2 (2 mL) and MeOH (2 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Satu- rated NaHCO3 solution (10 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3x10 mL) and the combined organic extracts were dried over Na2SO4 , filtered and concentrated in vacuo giving the deprotected alcohol as a slightly yellow oil, which was used in the next step without further purification. General Data: C49H66N2O13; FW: 890.46; TLC: Rf= 0.30 (CH2Cl2/MeOH 50:1); UV (+); Vanillin: black; = +24.93 (c = 1.4, CHCl3). 1
Figure imgf000072_0001
H-NMR (400 MHz, CDCl3): δ (ppm): 8.18 (s, 1H, NC=CH); 8.06 (s, 1H, NC=CH); 6.24-6.14 (m, 1H, CH2CH=CH); 6.03-6.92 (m, 3H, CH=CH); 5.88 (ddd, J = 15.9, 4.8, 2.0 Hz, 2H, CH=CH); 5.72-5.60 (m, 3H, CH=CH); 5.56 (d, J = 10.1 H, 1H, CH=CH); 5.44-5.32 (m, 2H, CH=CH); 5.25 (dd, J = 8.0, 5.2 Hz, 1H, CHOC=O); 4.70 (dd, J = 15.0, 6.7 Hz, 1H, 1OCH2OCH3); 4.45 (t, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.65 (dd, J = 6.5, 1.8 Hz, 1H, CHOCH2OCH3); 4.47 (d, J = 6.6 Hz, 1H, CHOCH2OCH3); 4.39 (d, J = 6.6 Hz, 1H, CHOCH2OCH3); 4.23-4.13 (m, 2H, CHOCH3); 3.90 (s, 3H, COOCH3); 3.89 (m, 1H, CHOCH2OCH3); 3.76 (d, J = 9.0 Hz, 1H, CHOCH2OCH3); 3.68 (dd, J = 10.3, 2.4 Hz, 1H, CHOH); 3.38 (s, 3H, CHOCH3); 3.32 (s, 3H, CHOCH3); 3.28 (s, 3H, CHOCH2OCH3); 3.27 (s, 3H, CHOCH2OCH3); 3.15-2.94 (m, 4H, CH2CHOCH3); 2.72-2.62 (m, 2H, CH2CH=CH); 2.58-2.48 (m, 1H, 1CH2CH=CH); 2.39-2.28 (m, 1H, 1CH2CH=CH); 1.74 (dd, J = 6.5, 1.4 Hz, 3H, CH=CHCH3); 1.71 (dd, J = 6.5, 1.4 Hz, 3H, CH=CHCH3); 1.03 (s, 3H, CCH3); 0.968 (s, 3H, CCH3); 0.921 (s, 3H, CCH3); 0.868 (s, 3H, CCH3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 162.6 (C=O); 162.5 (C=O); 161.8 (C=N); 160.8 (C=N); 144.2 (CH); 143.6 (CH); 143.2 (CH); 140.6 (CH); 140.4 (CH); 140.4 (CH); 133.6 (C); 133.5 (C); 132.1 (CH); 132.0 (CH); 127.1 (CH); 126.8 (CH); 113.9 (CH); 113.7 (CH); 111.1 (CH); 109.8 (CH); 93.8 (CH2); 93.6 (CH2); 91.4 (C); 91.2 (C); 88.3 (C); 88.0 (C); 84.7 (CH); 81.4 (CH); 79.3 (CH); 77.4 (CH); 77.0 (CH); 76.1 (CH); 57.0 (CH3); 56.9 (CH3); 56.2 (CH3); 56.1 (CH3); 52.3 (CH3); 41.8 (C); 41.0 (C); 34.7 (CH2); 34.7 (CH2); 32.8 (CH2); 31.4 (CH2); 21.1 (CH3); 19.9 (CH3); 19.8 (CH3); 19.5 (CH3); 18.1 (CH3); 18.0 (CH3). IR(neat): 3658 (br); 2980 (s); 2890 (m); 1737 (m); 1584 (m); 1463 (m); 1380 (m); 1258 (m); 1143 (s); 1098 (s); 1031 (s); 969 (m); 919 (m); 805 (m); 732 (m); 542 (w) cm-1. MS (ESI): m/z (%): 908.49 (100) [M+NH4]+, 891.46 (98) [M+H]+, 859.44 (35), 733.33 (7), 829.43 (5). HRMS (ESI) m/z: [M+H]+ Calcd for C49H67N2O13: 891.4643; found: 891.4768. The crude deprotected alcohol was dissolved in THF (1.5 mL) and treated at room temperature with LiOH (1 M in H2O, 0.165 mL, 0.165 mmol, 2.5 eq). The mixture was stirred overnight at room temperature and neutralized with 1 M HCl (1 mL). The aqueous phase was extracted with Et2O (3x3 mL) and the organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the seco-acid as a yellow wax, which was used without further purifi- cation. General Data: C48H64N2O13; FW: 876.44; TLC: UV (+); Vanillin: grey; =
Figure imgf000073_0001
+17.4 (c = 1.3, CHCl3). 1H-NMR (400 MHz, CDCl3): δ (ppm): 8.24 (s, 1H, NC=CH); 8.07 (s, 1H, NC=CH); 6.24-6.14 (m, 1H, CH2CH=CH); 6.04-5.93 (m, 3H, CH=CH); 5.93-5.81 (m, 2H, CH=CH); 5.73-5.60 (m, 3H, CH=CH); 5.55 (d, J = 10.5 Hz, 1H, CH=CH); 5.44-5.32 (m, 2H, CH=CH); 5.25 (dd, J = 8.6, 4.3 Hz, 1H, CHOC=O); 4.67 (d, J = 6.6 Hz, 2H, OCH2OCH3); 4.49 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.41 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.23-4.14 (m, 2H, CHOCH3); 3.92 (d, J = 8.8 Hz, 1H, CHOCH2OCH3); 3.76 (d, J = 9.1 Hz, 1H, CHOCH2OCH3); 3.70 (dd, J = 10.3, 2.6 Hz, 1H, CHOH); 3.39 (s, 3H, CHOCH3); 3.34 (s, 3H, CHOCH3); 3.30 (s, 3H, CHOCH2OCH3); 3.27 (s, 3H, CHOCH2OCH3); 3.19-2.94 (m, 4H, CH2CHOCH3); 2.75-2.61 (m, 2H, CH2CH=CH); 2.59-2.49 (m, 1H, 1CH2CH=CH); 2.42-2.29 (m, 1H, 1CH2CH=CH); 1.74 (dd, J = 6.5, 1.4 Hz, 3H, CH=CHCH3); 1.71 (dd, J = 6.5, 1.4 Hz, 3H, CH=CHCH3); 1.03 (s, 3H, CCH3); 0.975 (s, 3H, CCH3); 0.927 (s, 3H, CCH3); 0.877 (s, 3H, CCH3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 163.7 (C=O); 162.6 (C=O); 162.5 (C=N); 160.7 (C=N); 144.8 (CH); 143.7 (CH); 143.1 (CH); 140.5 (CH); 140.3 (CH); 133.5 (C); 133.2 (C); 132.2 (CH); 132.1 (CH); 127.1 (CH); 126.8 (CH); 125.7 (CH); 113.9 (CH); 113.8 (CH); 111.2 (CH); 109.9 (CH); 93.8 (CH3); 93.5 (CH3); 91.4 (C); 91.2 (C); 88.3 (C); 88.0 (C); 84.7 (CH); 81.6 (CH); 79.4 (CH); 79.3 (CH); 77.4 (CH); 76.3 (CH); 57.0 (CH3); 56.9 (CH3); 56.2 (CH3); 6.1 (CH3); 41.8 (C); 41.0 (C); 34.6 (CH2); 34.5 (CH2); 30.5 (CH2); 29.8 (CH2); 21.1 (CH3); 19.9 (CH3); 19.9 (CH3); 19.4 (CH3); 18.1 (CH3); 18.1 (CH3). IR(neat): 3658 (br); 2980 (s); 2923 (s); 2328 (w); 1719 (m); 1584 (m); 1461 (m); 1377 (m); 1251 (m); 1146 (m); 1098 (s); 1032 (s); 969 (s); 909 (m); 818 (w); 734 (s); 542 (w) cm-1. MS (ESI): m/z (%): 877.44 (100) [M+H]+, 894.47 (77) [M+NH4]+, 845.42 (49), 719.31 (30), 783.38 (23). HRMS (ESI) m/z: [M+H]+ Calcd for C48H65N2O13: 877.4487; found: 877.4473. The crude seco-acid was dissolved in THF (5 mL) and treated at room tem- perature with NEt3 (184 µL, 1.32 mmol, 20 eq) and 2,4,6-trichlorobenzoyl chloride (103 µL, 0.661 mmol, 10 eq). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added drop- wise to a solution of DMAP (323 mg, 2.64 mmol, 40 eq) in toluene (80 mL). The mixture was stirred overnight at room temperature and then quenched with saturated aqueous NH4Cl solution (20 mL) and water (20 mL) and the aqueous phase was extracted with EtOAc (3x40 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 2:1 to 1:1) to afford the macrocycle 35 (40 mg, 0.0462 mmol, 70% from 43) as a slightly yellow oil. General Data: C48H62N2O12; FW: 858.43; TLC: Rf= 0.50 (CH2Cl2/MeOH 50:1); UV (+); Vanillin: black; = +140.2 (c = 0.5, CHCl3
Figure imgf000074_0001
). 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.04 (s, 2H, NC=CH); 6.02-5.90 (m, 4H, CH=CH); 5.70- 5.60 (m, 4H, CH=CH); 5.51 (d, J = 10.3 Hz, 2H, CH=CH); 5.44-5.36 (m, 2H, CH=CH); 5.34 (dd, J = 11.0, 2.3 Hz, 2H, CHOC=O); 4.67 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.42 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.17- 4.08 (m, 2H, CHOCH3); 3.73 (d, J = 9.2 Hz, 2H, CHOCH2OCH3); 3.36 (s, 6H, CHOCH3); 3.34 (s, 6H, CHOCH2OCH3); 3.32-3.26 (m, 2H, CH2CH=CH); 3.06-2.88 (m, 4H, CH2CHOCH3); 2.43-2.35 (m, 2H, CH2CH=CH); 1.74 (dd, J = 6.1, 1.2 Hz, 6H, CH=CHCH3); 1.04 (s, 6H, CCH3); 1.00 (s, 6H, CCH3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 161.8 (C=O); 160.7 (C=N); 143.4 (CH); 141.3 (CH); 140.4 (CH); 133.8 (C); 132.0 (CH); 127.2 (CH); 113.7 (CH); 112.2 (CH); 93.8 (CH2); 91.0 (C); 87.9 (C); 81.5 (CH); 79.7 (CH); 76.4 (CH); 57.0 (CH3); 56.2 (CH3); 41.6 (C); 34.5 (CH2); 31.5 (CH2); 19.9 (CH3); 19.6 (CH3); 18.1 (CH3). IR(neat): 3172 (w); 3180 (w); 2930 (m); 2855 (m); 1736 (m); 1649 (m); 1584 (m); 1450 (m); 1368 (m); 1216 (m); 1140 (m); 1103 (s); 1031 (s); 973 (m); 921 (m); 830 (m); 752 (s) cm-1. MS (ESI): m/z (%): 859.44 (100) [M+H]+, 876.46 (42) [M+NH4]+, 797.40 (16), 735.36 (3). HRMS (ESI) m/z: [M+H]+ Calcd for C48H65N2O13: 859.4381; found: 859.4464. Example 40: Disorazole C1 (37) The intermediate product from Example 39 can be reacted according to the sequence of Example 33 followed by Example 34, as indicated above. The following Examples 41 to 52 disclose the synthesis of (4R)-Disorazole C1 (37r) Example 41: (4R,6S)-5,5-dimethyl-6,8-bis((triethylsilyl)oxy)oct-1-en-4-ol (12r)
Figure imgf000075_0001
A solution of (S,S)-Leighton reagent (4.74 g, 8.58 mmol, 1.2 eq) in CH2Cl2 (20 mL) was added to a solution of aldehyde 11 (2.67 g, 7.15 mmol, 1 eq) in CH2Cl2 (50 mL). Then Sc(OTf)3 (175 mg, 0.375 mmol, 0.05 eq) was added and the mixture was stirred for 24 h at room temperature. TBAF trihydrate (2.26 g, 7.15 mmol, 1 eq) was added and the mixture was stirred for 30 min at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (pentane/Et2O 50:1, then pentane/EtOAc/NEt31:1:0.1) to furnish the allylic alcohol 12r (2.53 g, 6.08 mmol, 85%) as a colorless liquid and the recovered diamine of the Leighton reagent (3.64 g, 8.08 mmol, 87 %) as a yellow paste. Analysis by 1H and 13C NMR showed a 13:1 mixture syn and anti diastereoisomers. General Data: C22H48O3Si2; FW: 416.31; TLC: Rf= 0.2 (Pentane/Et2O 50:1); UV (-); Vanillin: dark blue;
Figure imgf000076_0003
= -4.2 (c = 0.5, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 5.94-5.86 (m, 1H, CH=CH2); 5.13-5.05 (m, 2H, CH=CH2); 3.79 (dd, J = 6.5, 2.7 Hz, 1H, CHOH); 3.73 (m, 1H, 1CH2OSi); 3.65 (m, 1H, 1CH2OSi); 3.51 (dt, J = 10.5, 2.3 Hz, 1H, CHOSi); 2.74 (s, 1H, CHOH); 2.31-2.25 (m, 1H, 1CH2CH); 2.1-2.02 (m, 1H, 1CH2CH); 2.01-1.93 (m, 1H, 1CH2CH2O); 1.54-1.48 (m, 1H, 1CH2CH2O); 0.990-0.931 (m, 18H, 2OSi(CH2CH3)3); 0.897 (s, 3H, 1CCH3); 0.781 (s, 3H, 1CCH3); 0.650-0.570 (m, 12H, 2OSi(CH2CH3)3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 137.26 (CH); 116.74 (CH2); 75.78 (CH); 75.55 (CH); 61.24 (CH2); 42.57 (C); 36.60 (CH2); 36.51 (CH2); 18.86 (CH3); 18.64 (CH3); 7.22 (CH3); 6.88 (CH3); 5.64 (CH2); 4.42 (CH2). IR(neat): 3335 (br); 2955 (s); 2913 (s); 2877 (s); 1670 (w); 1642 (w); 1461 (m); 1415 (m); 1381 (m); 1238 (m); 1093 (s); 1056 (s); 1004 (s); 910 (m); 842 (m); 726 (s); 675 (m) cm-1. MS (ESI): m/z (%): 303.24 (100), 417.32 (23), 153.13 (16), 418.32 (8). HR-MS (ESI): calculated for C22H48O3Si2 [M+H]+: 417.3220, found: 417.3227. Example 42: (5R,7S)-5-allyl-11,11-diethyl-6,6-dimethyl-7-((triethylsilyl)oxy)-2,4,10- trioxa-11- silatridecane (13r)
Figure imgf000076_0001
MOMCl (1.3 mL, 17 mmol, 3 eq) was added dropwise at 0°C to a solution of allylic alcohol 12r (2.36 g, 5.67 mmol, 1 eq), DIPEA (3 mL, 17 mmol, 3 eq) and DMAP (207 mg, 1.7 mmol, 0.3 eq) in CH2Cl2 (60 mL). The mixture was stirred overnight at 45°C. Evaporation of the solvent and purification of the residue by flash chromatography (Pen/Et2O 60:1) afforded the protected triol 13r (2.4 g, 5.21 mmol, 92 %) as a colorless liquid. General Data: C24H52O4Si2; FW: 460.34; TLC: Rf= 0.5 (Pentane/Et2O 50:1); UV (-); Vanillin: dark blue;
Figure imgf000076_0002
= -10.67 (c = 0.75, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 5.95-5.87 (m, 1H, CH=CH2); 5.09-4.98 (m, 2H, CH=CH2); 4.61 (q, J = 6.7 Hz, 2H, OCH2OCH3); 3.74-3.68 (m, 1H, 1CH2OSi); 3.71 (dd, J = 8.6, 1.8 Hz, 1H, CHOCH2OCH3); 3.63.3.57 (m, 1H, 1CH2OSi); 3.47 (dd, J = 8.6, 2.9 Hz 1H, CHOSi); 3.36 (s, 3H, OCH3); 2.48- 2.41 (m, 1H, 1CH2CH); 2.23-2.14 (m, 1H, 1CH2CH); 1.91-1.83 (m, 1H, 1CH2CH2O); 1.55-1.48 (m, 1H, 1CH2CH2O); 1.00-0.923 (m, 18H, 2OSi(CH2CH3)3); 0.917 (s, 3H, 1CCH3); 0.811 (s, 3H, 1CCH3); 0.655-0.565 (m, 12H, 2OSi(CH2CH3)3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 137.44 (CH); 116.09 (CH2); 98.19 (CH2); 83.58 (CH); 74.63 (CH); 60.94 (CH2); 56.19 (CH3); 43.44 (C); 36.37 (CH2); 36.33 (CH2); 21.00 (CH3); 19.39 (CH3); 7.29 (CH3); 6.95 (CH3); 5.77 (CH2); 4.58 (CH2). IR(neat): 2954 (m); 2914 (m); 2877 (m); 1641 (w); 1461 (m); 1382 (m); 1238 (m); 1093 (s); 1035 (s); 1006 (s); 912 (m); 725 (s); 674 (m) cm-1. MS (EI, 70eV): m/z (%): 116.02 (100), 58.54 (64), 86.32 (50), 300.21 (45), 436.80 (9), 313.7 (6). HRMS (ESI) m/z: [M+H]+ Calcd for C24H52O4Si2: 461.3438; found: 461.3460. Example 43: (3S,5R,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl)oxy)non-7- en-1-ol (14r)
Figure imgf000077_0001
A solution of protected triol 13r (2.3 g, 5 mmol, 1 eq) and Grubbs II (212 mg, 0.250 mmol, 0.05 eq) in MeOH was stirred for 20 h at 60°C. The mixture was then concentrated in vacuo and the residue was filtered on a pad of silica gel (Pen/Et2O 1:1). The filtrate was concentrated in vacuo affording a mixture of 14r (80%) and 15r (15%) as a colorless liquid, which was used in the next step without further purification. A small amount was further purified by flash chromatography(Pen/Et2O 60:1 to 3:1) for analytical purpose. Analysis by 1H and 13C NMR showed a 14:1 mixture of E and Z isomers. General Data (15r): C24H52O4Si2; FW: 460.34; TLC: Rf= 0.5 (Pen- tane/Et2O 50:1); UV (-); Vanillin: dark blue;
Figure imgf000077_0002
= -44.0 (c = 0.2, CHCl3). 1H-NMR (15r) (400 MHz, CDCl3): δ (ppm): 5.64-5.54 (m, 1H, CH=CH); 5.31 (m, 1H, CH=CH); 4.66 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.43 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 3.86 (d, J = 8.7 Hz, 1H, CHOCH2OCH3); 3.75 (dd, J = 8.8, 2.4 Hz, 1H, CHOSi); 3.73-3.67 (m, 1H, 1CH2OSi); 3.64-3.55 (m, 1H, 1CH2OSi); 3.35 (s, 3H, OCH3); 1.94-1.82 (m, 1H, 1CH2CH2O); 1.71 (dd, J = 6.4, 1.4 Hz, 3H, CHCH3); 1.63-1.53 (m, 1H, 1CH2CH2O); 1.01-0.878 (m, 18H, 2OSi(CH2CH3)3); 0.922 (s, 3H, 1CCH3); 0.746 (s, 3H, 1CCH3); 0.668-0.540 (m, 12H, 2OSi(CH2CH3)3). 13C-NMR (15r) (100 MHz, CDCl3): δ (ppm): 130.84 (CH); 128.07 (CH); 93.53 (CH2); 81.31 (CH); 74.48 (CH); 61.29 (CH2); 55.91 (CH3); 42.38 (C); 35.92 (CH2); 20.31 (CH3); 19.54 (CH3); 17.98 (CH3); 7.31 (CH3); 6.95 (CH3); 5.83 (CH2); 4.56 (CH2). IR(neat) (15r): 2954 (m); 2918 (m); 2877 (m); 1730 (w); 1671 (w); 1632 (w); 1461 (m); 1415 (m); 1379 (m); 1239 (m); 1095 (s); 1033 (s); 973 (m); 922 (m); 823 (m); 726 (s) cm-1. MS (EI, 70eV): m/z (%): 116.02 (100), 58.54 (64), 86.32 (50), 300.21 (45), 436.80 (9), 313.7 (6). HRMS (ESI) m/z (15r): [M+H]+ Calcd for C24H53O4Si2: 461.3482; found: 461.3445. General Data (14r): C18H38O4Si; FW: 346.25; TLC: Rf= 0.3 (Pentane/Et2O 3:1); UV (-); Vanillin: dark blue;
Figure imgf000078_0001
= -69.0 (c = 0.8, CHCl3). 1H-NMR (12r) (400 MHz, CDCl3): δ (ppm): 5.64-5.54 (m, 1H, CH=CH); 5.31 (m, 1H, CH=CH); 4.62 (d, J = 6.5 Hz, 1H, 1OCH2OCH3); 4.43 (d, J = 6.5 Hz, 1H, 1OCH2OCH3); 3.87 (dd, J = 8.7, 2.4 Hz, 1H, CHOSi); 3.81 (d, J = 8.5 Hz, 1H, CHOCH2OCH3); 3.79-3.72 (m, 1H, 1CH2OSi); 3.71-3.62 (m, 1H, 1CH2OSi); 3.33 (s, 3H, OCH3); 1.95-1.84 (m, 1H, 1CH2CH2O); 1.71 (dd, J = 6.4, 1.5 Hz, 3H, CHCH3); 1.67-1.57 (m, 1H, 1CH2CH2O); 1.00-0.932 (m, 9H, OSi(CH2CH3)3); 0.923 (s, 3H, 1CCH3); 0.736 (s, 3H, 1CCH3); 0.678-0.583 (m, 6H, OSi(CH2CH3)3). 13C-NMR (12r) (100 MHz, CDCl3): δ (ppm): 131.02 (CH); 127.85 (CH); 93.71 (CH2); 81.89 (CH); 74.64 (CH); 61.02 (CH2); 55.85 (CH3); 42.23 (C); 35.43 (CH2); 20.25 (CH3); 19.24 (CH3); 17.96 (CH3); 7.25 (CH3); 5.74 (CH2). IR(neat) (12r): 3386 (br); 2954 (m); 2877 (m); 1669 (w); 1465 (m); 1415 (m); 1382 (m); 1238 (m); 1146 (m); 1091 (m); 1033 (s); 972 (m); 921 (m); 840 (m); 727 (s) cm-1. MS (ESI): m/z (%): 347.26 (100) [M+H]+, 317.25 (31), 348.26 (28), 369.24 (16) [M+Na]+, 285.22 (7). HR-MS (ESI): calculated for C18H39O4Si [M+H]+: 347.2618, found: 347.2620, 369.2435 [M+Na]+. Example 44: (3S,5R,E)-5-(methoxymethoxy)-4,4-dimethyl-3-((triethylsilyl)oxy)oct-6- enal (16r)
Figure imgf000079_0001
DMSO (0.780 mL, 11 mmol, 2 eq) in CH2Cl2 (5 mL) was added dropwise to a solution of oxalyl chloride (0.644 mL, 7.5 mmol, 1.5 eq) in CH2Cl2 (20 mL) at - 78°C. The mixture was stirred for 10 min at -78°C and then the crude 15r + 14r dissolved in CH2Cl2 (5 mL) was added dropwise. The reaction was stirred for 1 h at -78°C, quenched by dropwise addition of NEt3 (3.5 mL, 25 mmol, 5 eq) and then warmed to room temperature over 45 min. H2O (30 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3x20 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by flash chromatography (Pen/Et2O 10:1) afforded aldehyde 16r (1.33 g, 3.86 mmol, 77% from 13r) as a colorless liquid. General Data: C18H36O4Si; FW: 344.24; TLC: Rf= 0.3 (Pentane/Et2O 10:1); UV (-); Vanillin: grey;
Figure imgf000079_0002
= -54.87 (c = 0.8, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 9.84 (dd, J = 3.0, 1.2 Hz, 1H, CHO); 5.66-5.56 (m, 1H, CH=CH); 5.35-5.25 (m, 1H, CH=CH); 4.64 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.41 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.31 (dd, J = 7.2, 3.7 Hz, 1H, CHOSi); 3.78 (d, J = 8.7 Hz, 1H, CHOCH2OCH3); 3.33 (s, 3H, OCH3); 2.75 (ddd, J = 16.7, 3.7, 1.3 Hz, 1H, 1CH2CO); 2.58 (ddd, J = 16.7, 7.2, 3.0 Hz, 1H, 1CH2CO); 1.72 (dd, J = 6.5, 1.6 Hz, 3H, CHCH3); 0.973 (s, 3H, 1CCH3); 0.986-0.912 (m, 9H, OSi(CH2CH3)3); 0.777 (s, 3H, 1CCH3); 0.651-0.545 (m, 6H, OSi(CH2CH3)3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 202.90 (C=O); 131.62 (CH); 127.42 (CH); 93.43 (CH2); 81.50 (CH); 72.15 (CH); 56.10 (CH3); 47.95 (CH2); 42.27 (C); 20.19 (CH3); 19.89 (CH3); 17.97 (CH3); 7.14 (CH3); 5.50 (CH2). IR(neat): 3017 (w); 2952 (m); 2877 (m); 2716 (w); 1727 (s); 1464 (m); 1381 (w); 1238 (w); 1096 (s); 1074 (s); 1030 (s); 972 (m); 921 (m); 823 (m); 726 (s) cm-1. MS (ESI): m/z (%): 362.27 (100) [M+Na]+, 367.22 (76), 345.24 (28) [M+H]+, 369.24 (16), 285.22 (7). HR-MS (ESI): calculated for C18H36O4Si [M+H]+: 345.2461, found: 345.2460, 362.2727 [M+NH4]+. Example 45: (5R,7S)-9,9-diethyl-7-((Z)-3-iodoallyl)-6,6-dimethyl-5-((E)-prop-1-en-1- yl)-2,4,8-trioxa-9-silaundecane (17r)
Figure imgf000080_0001
NaHMDS (1 M in THF, 4.2 mL, 4.2 mmol, 1.5 eq) was added dropwise at 0°C to a solution of IMePPh3I (2.22 g, 4.2 mmol, 1.5 eq) in THF (30 mL). The red solution was stirred for 10 min at room temperature and then cooled to -78°C. DMPU (2.5 mL, 20.93 mmol, 7.5 eq) was added dropwise, followed by alde- hyde 16r (960 mg, 2.79 mmol, 1 eq) in THF (7 mL). The mixture was stirred for 1 h at -78°C and 30 min at room temperature. Saturated NH4Cl solution was added and the aqueous phase was extracted with Et2O (3x25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Pen/Et2O 100:1) giving the Z Iodide 17r (875 mg, 1.87 mmol, 67%) as a slightly yellow liquid. General Data: C19H37IO3Si; FW: 468.16; TLC: Rf= 0.25 (Pentane/Et2O 100:1); UV (-); Vanillin: black;
Figure imgf000080_0002
= -30.133 (c = 0.75, CHCl3). 1H-NMR (400 MHz, CDCl3): δ (ppm): 6.36 (q, J = 7.3 Hz, 1H, CH=CHI); 6.21 (dt, J = 7.4, 1.7 Hz, 1H, CH=CHI); 5.69-5.58 (m, 1H, CH=CH); 5.33 (m, 1H, CH=CH); 4.68 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.45 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 3.90-3.84 (m, 2H, 2CHOR); 3.36 (s, 3H, OCH3); 2.44-2.38 (m, 2H, CH2CH); 1.73 (dd, J = 6.5, 1.6 Hz, 3H, CHCH3); 1.02-0.922 (m, 9H, OSi(CH2CH3)3); 0.944 (s, 3H, 1CCH3); 0.769 (s, 3H, 1CCH3); 0.658-0.559 (m, 6H, OSi(CH2CH3)3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 140.30 (CH); 131.17 (CH); 127.88 (CH); 93.59 (CH2); 82.72 (CH); 81.56 (CH); 75.77 (CH); 56.04 (CH3); 42.81 (C); 38.76 (CH2); 20.32 (CH3); 19.75 (CH3); 17.99 (CH3); 7.27 (CH3); 5.72 (CH2). IR(neat): 3016 (w); 2919 (m); 2876 (m); 1665 (w); 1465 (m); 1415 (m); 1381 (w); 1238 (m); 1093 (s); 1033 (s); 972 (m); 922 (m); 822 (w); 724 (s) cm-1. MS (ESI): m/z (%): 506.53 (100), 507.53 (45), 504.51 (22), 469.16 (8) [M+H]+, 457.16 (5), 396.31 (4). HR-MS (ESI): calculated for C19H38IO3Si [M+H]+: 469.1635, found: 469.1631. Example 46: Methyl 2-((2R,3E,7Z,10S,12R,13E)-2-methoxy-12-(methoxymethoxy)- 11,11-dimethyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1- yl)oxazole-4-carboxylate (40r)
Figure imgf000081_0001
The vinyl iodide 17r (397 mg, 0.847 mmol, 1 eq) was dissolved in degassed CH3CN (5 mL) and CuI (39 mg, 0.254 mmol, 0.3 eq) and PdCl2(PPh3)2 (60 mg, 0.0847 mmol, 0.1 eq) were added. The mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -10°C. NEt3 (0.706 mL, 5.08 mmol, 6 eq) was added, followed by a slow addition of the enyne 29r (240 mg, 1.02 mmol, 1.2 eq) in degassed CH3CN (3 mL). The solution became red and af- ter 15 min the bath was removed. The mixture was stirred for 1 h at room temperature and quenched with saturated aqueous NH4Cl solution (10 mL). The aqueous phase was extracted with Et2O (3x10 mL) and the combined or- ganic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (pentane/Et2O 2:1) to give the monomer 40r (448 mg, 0.779 mmol, 92 %) as a slightly yellow oil. General Data: C31H49NO7Si; FW: 575.33; TLC: Rf= 0.20 (pentane/Et2O 2:1); UV (+); Vanillin: black; = -13.00 (c = 0.8, CHCl3
Figure imgf000081_0002
). 1H-NMR (400 MHz, CDCl3): δ (ppm): 8.15 (s, 1H, NC=CH); 6.14-6.05 (m, 1H, CH2CH=CH); 5.99 (dd, J = 15.8, 7.4 Hz, 1H, CCH=CHCH); 5.88 (dd, J = 15.9, 2.1 Hz, 1H, CCH=CHCH2); 5.66- 5.54 (m, 2H, CH(OCH3)CH=CH, CH=CHCH3); 5.36-5.27 (m, 1H, CH=CHCH3); 4.66 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.43 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.20-4.13 (m, 1H, CHOCH3); 3.90 (s, 3H, COOCH3); 3.89 (app t, J = 6.2 Hz, 1H, CHOCH2OCH3); 3.82 (t, J = 5.3 Hz, 1H, CH2CHOTES); 3.33 (s, 3H, CHOCH3); 3.26 (s, 3H, CHOCH2OCH3); 3.10 (dd, J = 15.0, 7.9 Hz, 1H, 1CH2CHOCH3); 2.98 (dd, J = 15.0, 5.5 Hz, 1H, 1CH2CHOCH3); 2.62-2.54 (m, 2H, CH2CH=CH); 1.71 (dd, J = 6.4, 1.5 Hz, 3H, CH=CHCH3); 0.957 (app t, J = 8.0 Hz, 9H, OSi(CH2CH3)3); 0.938 (s, 3H, CCH3); 0.765 (s, 3H, CCH3); 0.600 (q, J = 7.8 Hz, 6H, OSi(CH2CH3)3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 162.61 (C=O); 161.79 (C=N); 144.11 (CH); 143.47 (CH); 140.30 (CH); 133.50 (C); 130.96 (CH); 128.03 (CH); 113.98 (CH); 109.39 (CH); 93.56 (CH2); 91.27 (C); 88.53 (C); 81.48 (CH); 79.42 (CH); 76.51 (CH); 56.92 (CH3); 55.92 (CH3); 52.26 (CH3); 42.87 (C); 34.74 (CH2); 34.40 (CH2); 20.22 (CH3); 19.67 (CH3); 17.98 (CH3); 7.25 (CH3); 5.72 (CH2). IR(neat): 3237 (m); 2954 (m); 2878 (m); 1750 (m); 1583 (m); 1536 (m); 1397 (s); 1238 (m); 1140 (m); 1093 (s); 1033 (s); 1006 (s); 956 (m); 922 (m); 725 (m); 670 (m); 609 (w) cm-1. MS (ESI): m/z (%): 593.36 (100) [M+NH4]+, 418.20 (54), 514.30 (48), 350.17 (8), 482.27 (6), 576.33 (2) [M+H]+. HR-MS (ESI): calculated for C31H50NO7Si [M+H]+: 576.3357, found: 576.3365, 593.3646 [M+NH4]+. Example 47: Methyl 2-((2R,3E,7Z,10S,12R,13E)-10-hydroxy-2-methoxy-12-(methox- ymethoxy)-11,11- dimethylpentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4- carboxylate (31r)
Figure imgf000083_0001
CSA (13 mg, 0.0521 mmol, 0.2 eq) was added at 0°C to a solution of TES protected monomer 40r (150 mg, 0.261 mmol, 1 eq) in CH2Cl2 (7 mL) and MeOH (7 mL). The mixture was stirred for 1 h at 0°C under normal atmos- phere. Saturated aqueous NaHCO3 solution (15 mL) was added and the lay- ers were separated. The aqueous phase was extracted with CH2Cl2 (3x10 mL) and the combined organic extracts were dried over Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (Et2O/pentane 2:1) giving deprotected monomer 31r (102 mg, 0.222 mmol, 85%) as a slightly yellow oil. General Data: C25H35NO7; FW: 461.24; TLC: Rf= 0.25 (Et2O/Pentane 2:1); UV (+); Vanillin: black;
Figure imgf000083_0002
= -81.07 (c = 0.75, CHCl3). 1H-NMR (400 MHz, CDCl3): δ (ppm): 8.15 (s, 1H, NC=CH); 6.19-6.08 (m, 1H, CH2CH=CH); 5.96 (dd, J = 15.8, 7.3 Hz, 1H, CCH=CHCH); 5.86 (dd, J = 15.9, 2.0 Hz, 1H, CCH=CHCH2); 5.73- 5.61 (m, 2H, CH(OCH3)CH=CH, CH=CHCH3); 5.37-5.27 (m, 1H, CH=CHCH3); 4.71 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.46 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.21-4.11 (m, 1H, CHOCH3); 3.90 (s, 3H, COOCH3); 3.89 (app dd, J = 6.7, 2.0 Hz, 1H, CHOCH2OCH3); 3.62 (dd, J = 10.1, 2.8 Hz, 1H, CH2CHOH); 3.37 (s, 3H, CHOCH3); 3.26 (s, 3H, CHOCH2OCH3); 3.10 (dd, J = 14.9, 7.8 Hz, 1H, 1CH2CHOCH3); 2.99 (dd, J = 14.9, 5.6 Hz, 1H, 1CH2CHOCH3); 2.61- 2.50 (m, 1H, 1CH2CH=CH); 2.43-2.33 (m, 1H, 1CH2CH=CH); 1.74 (dd, J = 6.5, 1.7 Hz, 3H, CH=CHCH3); 0.973 (s, 3H, CCH3); 0.807 (s, 3H, CCH3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 162.54 (C=O); 161.76 (C=N); 144.12 (CH); 142.67 (CH); 140.41 (CH); 133.49 (C); 132.47 (CH); 127.08 (CH); 113.88 (CH); 110.26 (CH); 93.21 (CH2); 91.23 (C); 88.17 (C); 84.83 (CH); 79.37 (CH); 77.97 (CH); 56.96 (CH3); 56.15 (CH3); 52.26 (CH3); 41.23 (C); 34.70 (CH2); 33.04 (CH2); 21.50 (CH3); 17.98 (CH3); 16.20 (CH3). IR(neat): 3489 (br); 3159 (w); 3020 (m); 2937 (m); 2826 (w); 2246 (w); 1737 (m); 1585 (m); 1438 (m); 1322 (m); 1221 (m); 1167 (m); 1098 (s); 1032 (s); 913 (s); 806 (m); 730 (s); 646 (m); 542 (w) cm-1. MS (ESI): m/z (%): 304.11 (100), 479.27 (80) [M+NH4]+, 272.09 (77), 400.21 (48), 430.22 (30), 462.24 (28) [M+H]+, 368.18 (27), 209.13 (3). HR-MS (ESI): calculated for C25H36NO7 [M+H]+: 462.2492, found: 462.2482, 479.2748 [M+NH4]+. Example 48: 2-((2R,3E,7Z,10S,12R,13E)-2-methoxy-12-(methoxymethoxy)-11,11-dime- thyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4-car- boxylic acid (42r)
Figure imgf000084_0001
31r (150 mg, 0.261 mmol, 1 eq) was dissolved in THF (5 mL) and treated at room temperature with LiOH (1 M in H2O, 0.783 mL, 0.783 mmol, 3 eq). The mixture was stirred for 3 h at room temperature and neutralized with 1 M HCl (2 mL). The aqueous phase was extracted with Et2O (3x3 mL) and the or- ganic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give acid 42r (146 mg, 0.259 mmol, 99%) as a slightly yellow oil, which was used for the next step without further purification. General Data: C30H47NO7Si; FW: 561.31; TLC: UV (+); Vanillin: black. 1H-NMR (400 MHz, CDCl3): δ (ppm): 8.23 (s, 1H, NC=CH); 6.16-6.07 (m, 1H, CH2CH=CH); 6.00 (dd, J = 15.7, 7.4 Hz, 1H, CCH=CHCH); 5.89 (dd, J = 15.8, 1.9 Hz, 1H, CCH=CHCH2); 5.64- 5.56 (m, 2H, CH(OCH3)CH=CH, CH=CHCH3); 5.35-5.29 (m, 1H, CH=CHCH3); 4.67 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.44 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.20-4.15 (m, 1H, CHOCH3); 3.89 (d, J = 8.9 Hz, 1H, CHOCH2OCH3); 3.82 (t, J = 5.2 Hz, 1H, CHOTES); 3.35 (s, 3H, CHOCH3); 3.28 (s, 3H, CHOCH2OCH3); 3.12 (dd, J = 15.0, 7.8 Hz, 1H, 1CH2CHOCH3); 3.02 (dd, J = 15.1, 5.6 Hz, 1H, 1CH2CHOCH3); 2.62-2.54 (m, 2H, 1CH2CH=CH); 1.72 (dd, J = 6.5, 1.4 Hz, 3H, CH=CHCH3); 0.959 (t, J = 8.0 Hz, 9H, OSi(CH2CH3)3); 0.943 (s, 3H, CCH3); 0.771 (s, 3H, CCH3); 0.604 (q, J = 7.9 Hz, 6H, OSi(CH2CH3)3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 164.0 (C=O); 162.8 (C=N); 144.9 (CH); 143.5 (CH); 140.1 (CH); 132.9 (C); 131.0 (CH); 128.0 (CH); 114.1 (CH); 109.4 (CH); 93.5 (CH2); 91.2 (C); 88.6 (C); 81.6 (CH); 79.3 (CH); 76.6 (CH); 56.9 (CH3); 55.9 (CH3); 42.9 (C); 34.4 (CH2); 30.5 (CH2); 20.3 (CH3); 19.7 (CH3); 18.0 (CH3); 7.3 (CH3); 5.7 (CH2). IR(neat): 3026 (w); 2934 (br); 2876 (m); 1723 (m); 1586 (m); 1463 (m); 1360 (w); 1214 (w); 1143 (m); 1095 (s); 1033 (s); 973 (m); 921 (m); 766 (m); 6728 (s); 546 (w) cm-1. MS (ESI): m/z (%): 404.18 (100), 579.34 (78) [M+NH4]+, 500.28 (51), 372.16 (27), 468.25 (10), 336.15 (8), 562.32 (3) [M+H]+. HR-MS (ESI): calculated for C30H48NO7Si [M+H]+: 562.3200, found: 562.3199, 579.3453 [M+NH4]+. Example 49: (2E,4R,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)oxazol-2-yl)- 4- (methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn-6-yl 2- ((2R,3E,7Z,10S,12R,13E)-2-methoxy-12-(methoxymethoxy)-11,11-dime- thyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)oxazole-4-car- boxylate (43r)
Figure imgf000086_0001
The crude acid 42r (91 mg, 0.162 mmol, 1.5 eq) was dissolved in THF (5 mL) treated at room temperature with NEt3 (90 µL, 0.648 mmol, 6 eq) and 2,4,6- trichlorobenzoyl chloride (68 µL,0.432 mmol, 4 eq). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added dropwise to a solution of alcohol 31r (50 mg, 0.108 mmol, 1 eq) and DMAP (79 mg, 0.648 mmol, 6 eq) in toluene (5 mL). The mixture was stirred overnight at room temperature and then quenched with saturated aqueous NH4Cl solution (15 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Et2O/pentane 2:1) to afford the dimer 43r (81 mg, 0.0813 mmol, 75%) as a slightly yellow oil. General Data: C55H80N2O13Si; FW: 1004.54; TLC: Rf = 0.30 (Et2O/pentane 2:1); UV (+); Vanillin: black. 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.18 (s, 1H, NC=CH); 8.07 (s, 1H, NC=CH); 6.15-6.05 (m, 1H, CH2CH=CH); 6.05-5.84 (m, 5H, CH=CH); 5.66- 5.53 (m, 4H, CH=CH); 5.38-5.29 (m, 2H, CH=CH); 5.28 (app dd, J = 5.3, 1.7 Hz, 1H, CHOC=O); 4.68 (dd, J = 7.0, 6.7 Hz, 1H, 1OCH2OCH3); 4.45 (dd, J = 6.9, 4.7 Hz, 1H, 1OCH2OCH3); 4.24-4.14 (m, 2H, CHOCH3); 3.90 (s, 3H, COOCH3); 3.89 (app d, J = 7.8 Hz, 1H, CH2CHOTES); 3.82 (m, 2H, CHOCH2OCH3); 3.38 (s, 3H, CHOCH3); 3.34 (s, 3H, CHOCH3); 3.29 (s, 3H, CHOCH2OCH3); 3.28 (s, 3H, CHOCH2OCH3); 3.17-2.98 (m, 4H, CH2CHOCH3); 2.76-2.69 (m, 2H, CH2CH=CH); 2.62-2.56 (m, 2H, CH2CH=CH); 1.71 (dd, J = 6.4, 1.3 Hz, 6H, CH=CHCH3); 1.02 (s, 3H, CCH3); 0.977 (s, 3H, CCH3); 0.951 (app t, J = 5.6 Hz, 9H, OSi(CH2CH3)3); 0.938 (s, 3H, CCH3); 0.771 (s, 3H, CCH3); 0.602 (q, J = 7.7 Hz, 6H, OSi(CH2CH3)3). IR(neat): 2953 (m); 2879 (m); 2284 (w); 1737 (m); 1583 (m); 1439 (m); 1318 (m); 1168 (m); 1099 (s); 1033 (s); 911 (s); 807 (m); 728 (s); 647 (m); 551 (w) cm-1. MS (ESI): m/z (%): 1005.55 (100) [M+H]+, 1022.56 (760) [M+NH4]+, 943.52 (45), 973.53 (28), 847.43 (8). HRMS (ESI) m/z: [M+H]+ Calcd for C55H81N2O13Si: 1005.5508; found: 1005.5594. Example 50: (16,16’)-(4R-bis(methoxymethyl))-(9,10,9’,10’)-tetradehydridodisorazole C1 (35r)
Figure imgf000087_0001
CSA (3 mg, 0.0132 mmol, 0.2 eq) was added at 0°C to a solution TES pro- tected dimer 43r (67 mg, 0.0661 mmol, 1 eq) in CH2Cl2 (2 mL) and MeOH (2 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Satu- rated NaHCO3 solution (10 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3x10 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo giving the deprotected alcohol as a slightly yellow oil, which was used in the next step without further purification. General Data: C49H66N2O13; FW: 890.46; TLC: Rf= 0.20 (CH2Cl2/MeOH 100:1); UV (+); Vanillin: black;
Figure imgf000088_0001
= -22.83 (c = 0.6, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.17 (s, 1H, NC=CH); 8.05 (s, 1H, NC=CH); 6.19-6.09 (m, 1H, CH2CH=CH); 6.03-5.83 (m, 5H, CH=CH); 5.70- 5.51 (m, 4H, CH=CH); 5.37-5.25 (m, 2H, CH=CH); 5.28 (app dd, J = 5.3, 1.7 Hz, 1H, CHOC=O); 4.70 (dd, J = 15.0, 6.7 Hz, 1H, 1OCH2OCH3); 4.45 (t, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.22-4.13 (m, 2H, CHOCH3); 3.90 (s, 3H, COOCH3); 3.89 (app d, J = 9.0 Hz, 1H, CHOCH2OCH3); 3.82 (d, J = 8.7 Hz, 1H, CHOCH2OCH3); 3.62 (dt, J = 10.0, 2.7 Hz, 1H, CHOH); 3.37 (s, 6H, CHOCH3); 3.28 (s, 3H, CHOCH2OCH3); 3.27 (s, 3H, CHOCH2OCH3); 3.15-2.96 (m, 4H, CH2CHOCH3); 2.78-2.64 (m, 2H, CH2CH=CH); 2.61-2.51 (m, 1H, 1CH2CH=CH); 2.45-2.33 (m, 1H, 1CH2CH=CH); 1.74 (dd, J = 6.5, 1.6 Hz, 3H, CH=CHCH3); 1.71 (dd, J = 6.5, 1.6 Hz, 3H, CH=CHCH3); 1.02 (s, 3H, CCH3); 0.977 (s, 3H, CCH3); 0.944 (s, 3H, CCH3); 0.813 (s, 3H, CCH3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.59 (C=O); 162.50 (C=O); 161.76 (C=N); 160.77 (C=N); 144.17 (CH); 143.64 (CH); 142.65 (CH); 140.62 (CH); 140.55 (CH); 133.55 (C); 133.49 (C); 132.52 (CH); 132.32 (CH); 127.06 (CH); 126.90 (CH); 125.65 (CH); 113.81 (CH); 113.75 (CH); 111.23 (CH); 110.27 (CH); 93.48 (CH2); 93.19 (CH2); 91.41 (C); 91.30 (C); 88.13 (C); 88.09 (C); 84.86 (CH); 81.50 (CH); 79.33 (CH); 78.00 (CH); 77.37 (CH); 57.01 (CH3); 56.99 (CH3); 56.16 (CH3); 52.28 (CH3); 41.76 (C); 41.22 (C); 34.69 (CH2); 34.09 (CH2); 33.03 (CH2); 31.21 (CH2); 21.53 (CH3); 20.07 (CH3); 19.60 (CH3); 18.07 (CH3); 18.00 (CH3); 16.17 (CH3). IR(neat): 3327 (br); 3165 (w); 2928 (m); 2853 (m); 1736 (s); 1583 (m); 1439 (m); 1370 (m); 1314 (m); 1241 (m); 1143 (m); 1099 (s); 1031 (s); 972 (m); 920 (m); 883 (w); 762 (m); 724 (m); 542 (m) cm-1. MS (ESI): m/z (%): 908.49 (100) [M+NH4]+, 891.46 (83) [M+H]+, 733.33 (41), 797.40 (25), 671.29 (7). HR-MS (ESI): calculated for C49H67N2O13 [M+H]+: 891.4643, found: 891.4648, 908.4911 [M+NH4]+. The crude deprotected alcohol was dissolved in THF (1.5 mL) and treated at room temperature with LiOH (1 M in H2O, 0.165 mL, 0.165 mmol, 2.5 eq). The mixture was stirred overnight at room temperature and neutralized with 1 M HCl (1 mL). The aqueous phase was extracted with Et2O (3x3 mL) and the organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the seco-acid as a yellow wax, which was used without further purifi- cation. General Data: C48H64N2O13; FW: 876.44; TLC: UV (+); Vanillin: grey;
Figure imgf000089_0001
-26.4 (c = 0.5,CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.20 (s, 1H, NC=CH); 8.10 (s, 1H, NC=CH); 6.18-6.09 (m, 1H, CH2CH=CH); 6.04-5.80 (m, 5H, CH=CH); 5.73- 5.52 (m, 4H, CH=CH); 5.38-5.26 (m, 3H, CH=CH, CHOC=O); 4.71 (dd, J = 13.5, 6.8 Hz, 1H, 1OCH2OCH3); 4.46 (dd, J = 6.7, 3.8 Hz, 1H, 1OCH2OCH3); 4.24-4.13 (m, 2H, CHOCH3); 3.90 (d, J = 9.1 Hz, 1H, CHOCH2OCH3); 3.83 (d, J = 8.7 Hz, 1H, CHOCH2OCH3); 3.64 (dd, J = 9.8, 2.8 Hz, 1H, CHOH); 3.39 (s, 3H, CHOCH3); 3.38 (s, 3H, CHOCH3); 3.30 (s, 3H, CHOCH2OCH3); 3.28 (s, 3H, CHOCH2OCH3); 3.18-2.94 (m, 4H, CH2CHOCH3); 2.82-2.51 (m, 3H, 3CH2CH=CH); 2.47-2.33 (m, 1H, 1CH2CH=CH); 1.74 (dd, J = 6.5, 1.6 Hz, 3H, CH=CHCH3); 1.71 (dd, J = 6.4, 1.3 Hz, 3H, CH=CHCH3); 1.03 (s, 3H, CCH3); 0.983 (s, 3H, CCH3); 0.950 (s, 3H, CCH3); 0.815 (s, 3H, CCH3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.56 (C=O); 162.23 (C=O); 160.74 (C=N); 157.69 (C=N); 144.49 (CH); 143.88 (CH); 142.58 (CH); 140.58 (CH); 140.50 (CH); 133.60 (C); 133.47 (C); 132.61 (CH); 132.36 (CH); 126.99 (CH); 126.84 (CH); 125.65 (CH); 113.86 (CH); 113.78 (CH); 111.38 (CH); 110.33 (CH); 93.53 (CH3); 93.17 (CH3); 91.38 (C); 91.33 (C); 88.14 (C); 88.05 (C); 84.91 (CH); 81.67 (CH); 79.46 (CH); 79.28 (CH); 78.12 (CH); 77.36 (CH); 56.99 (CH3); 56.98 (CH3); 56.16 (CH3); 56.13 (CH3); 41.77 (C); 41.21 (C); 34.64 (CH2); 33.01 (CH2); 31.28 (CH2); 29.84 (CH2); 21.56 (CH3); 20.02 (CH3); 19.50 (CH3); 18.09 (CH3); 18.01 (CH3); 16.16 (CH3). IR(neat): 3323 (br); 2929 (m); 2851 (m); 2249 (w); 1731 (m); 1583 (m); 1438 (m); 1364 (m); 1310 (m); 1143 (m); 1100 (s); 1030 (s); 972 (m); 910 (m); 837 (w); 730 (s); 646 (m) cm-1. MS (ESI): m/z (%): 877.44 (100) [M+H]+, 894.47 (77) [M+NH4]+, 845.42 (49), 719.31 (30), 783.38 (23). HR-MS (ESI): calculated for C48H65N2O13 [M+H]+: 877.4487, found: 877.4478, 894.4744 [M+NH4]+. The crude seco-acid was dissolved in THF (5 mL) and treated at room tem- perature with NEt3 (184 µL, 1.32 mmol, 20 eq) and 2,4,6-trichlorobenzoyl chloride (103 µL, 0.661 mmol, 10 eq). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added dropwise to a solution of DMAP (323 mg, 2.64 mmol, 40 eq) in toluene (80 mL). The mixture was stirred overnight at room temperature and then quen- ched with saturated aqueous NH4Cl solution (20 mL) and water (20 mL) and the aqueous phase was extracted with EtOAc (3x40 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 2:1 to 1:1) to afford the macrocycle 35r (40 mg, 0.0462 mmol, 70% from 43r) as a slightly yellow oil. General Data: C48H62N2O12; FW: 858.43; TLC: Rf= 0.50 (CH2Cl2/MeOH 50:1); UV (+); Vanillin: black; = +53.7 (c = 1.00, CHCl3).
Figure imgf000090_0001
1H-NMR (600 MHz, CDCl3): δ (ppm): 8.04 (s, 2H, NC=CH); 6.03-5.88 (m, 4H, CH=CH); 5.70-5.47 (m, 6H, CH=CH); 5.44-5.23 (m, 2H, CH=CH); 5.40 (dd, J = 11.2, 2.4 Hz, 2H, CHOC=O); 4.69 (d, J = 7.0 Hz, 1H, 1OCH2OCH3); 4.45 (d, J = 7.0 Hz, 1H, 1OCH2OCH3); 4.17-3.99 (m, 2H, CHOCH3); 3.81 (d, J = 8.8 Hz, 2H, CHOCH2OCH3); 3.38 (s, 6H, CHOCH3); 3.36 (s, 6H, CHOCH2OCH3); 3.34-3.25 (m, 2H, CH2CH=CH); 3.07-2.83 (m, 4H, CH2CHOCH3); 2.53-2.43 (m, 2H, CH2CH=CH); 1.73 (dd, J = 6.3, 1.3 Hz, 6H, CH=CHCH3); 1.03 (s, 6H, CCH3); 0.962 (s, 6H, CCH3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 161.77 (C=O); 160.66 (C=N); 143.46 (CH); 141.27 (CH); 140.44 (CH); 133.74 (C); 132.51 (CH); 126.79 (CH); 113.64 (CH); 112.21 (CH); 93.51 (CH 2 ); 90.94 (C); 87.89 (C); 81.61 (CH); 79.71 (CH); 77.36 (CH); 56.99 (CH3); 56.21 (CH3); 41.57 (C); 34.51 (CH2); 31.09 (CH2); 19.99 (CH3); 19.44 (CH3); 18.08 (CH3). IR(neat): 3168 (w); 2933 (m); 2855 (m); 2249 (w); 1736 (m); 1690 (m); 1582 (m); 1441 (m); 1365 (m); 1308 (m); 1141 (m); 1099 (s); 1028 (s); 988 (m); 914 (m); 805 (m); 730 (s) cm-1. MS (ESI): m/z (%): 859.43 (100) [M+H]+, 876.46 (32) [M+NH4]+, 797.40 (20), 735.36 (3). HR-MS (ESI): calculated for C48H65N2O13 [M+H]+: 859.4381, found: 859.4366, 876.4633 [M+NH4]+. Example 51 (16,16’)-(4R-bis(methoxymethyl))-disorazole C1 (36r)
Figure imgf000091_0001
Nitrogen was bubbled for 15 min through a suspension of Zinc (3 g, 45.88 mmol) in H2O (18 mL) and then Cu(OAc)2·H2O (300 mg, 1.50 mmol) was ad- ded at room temperature and after 15 min AgNO3 (300 mg, 1.77 mmol) was added (exothermic reaction). The mixture was stirred for 30 min at room tem- perature, filtered by suction and washed with H2O (30 mL), MeOH (20 mL), acetone (20 mL) and Et2O (20 mL). This activated zinc solids were added to a solution of 35r (20 mg, 0.0233 mmol) in MeOH/H2O 1:1 (5 mL). The mix- ture was stirred for 24 h at 50°C and then filtered on a pad of silica and washed with MeOH. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (CH2Cl2/MeOH 60:1) to afford 36r (13 mg, 0.0151, 65%) as a colorless oil. General Data: C48H66N2O12; FW: 862.46; TLC: Rf= 0.40 (CH2Cl2/MeOH 50:1); UV (+); Vanillin: dark green; = -43.3 (c = 0.35, CHCl3). 1
Figure imgf000091_0002
H-NMR (600 MHz, CDCl3): δ (ppm): 7.89 (s, 2H, NC=CH); 6.44 (dd, J = 15.2, 11.3 Hz, 2H, CH(OCH3)CH=CH); 6.34 (app t, J = 11.3 Hz, 2H, CH2CH=CH); 6.21 (dd, J = 11.5, 11.0 Hz, 2H, CHCH=CHCH); 5.90 (dd, J = 11.2, 11.0 Hz, 2H, CHCH=CHCH); 5.61 (dd, J = 15.4, 6.5 Hz, 2H, CH3CH=CH); 5.54 (dd, J = 15.1, 8.6 Hz, 2H, CH3CH=CH); 5.38 (dd, J = 10.8, 2.5 Hz, 2H, CHOC=O); 5.32 (dd, J = 8.8, 1.7 Hz, 2H, CH(OCH3)CH=CH); 5.29 (dd, J = 8.6, 1.5 Hz, 2H, CH2CH=CH); 4.68 (d, J = 6.9 Hz, 1H, 1OCH2OCH3); 4.43 (d, J = 6.9 Hz, 1H, 1OCH2OCH3); 4.15-4.10 (app q, J = 14.9, 6.7 Hz, 2H, CHOCH3); 3.81 (d, J = 8.7 Hz, 2H, CHOH); 3.36 (s, 6H, CHOCH2OCH3); 3.26 (s, 6H, CHOCH3); 3.12 (dd, J = 14.8, 6.0 Hz, 2H, CH2CHOCH3); 2.78 (dd, J = 14.8, 7.2 Hz, 2H, CH2CHOCH3); 2.63-2.50 (m, 4H, CH2CH=CH); 1.73 (dd, J = 6.5, 1.3 Hz, 3H, CH=CHCH3); 0.984 (s, 6H, CCH3); 0.919 (s, 6H, CCH3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 162.36 (C=O); 160.73 (C=N); 143.34 (CH); 133.47 (C); 133.18 (CH); 132.41 (CH); 130.27 (CH); 129.11 (CH); 128.09 (CH); 126.87 (CH); 125.73 (CH);125.68 (CH); 93.40 (CH2); 81.44 (CH); 79.94 (CH); 77.58 (CH); 56.69 (CH3); 56.27 (CH3); 41.59 (C); 35.21 (CH2); 28.07 (CH2); 20.10 (CH3); 19.60 (CH3); 18.09 (CH3). MS (ESI): m/z (%): 861.46 (100) [M+H]+, 282.28 (70), 880.49 (32) [M+NH4]+. HR-MS (ESI): calculated for C48H67N2O12 [M+H]+: 863.4694, found 863.4672, 880.4945 [M+NH4]+. Example 52: (4R)-Disorazole C1 (31r)
Figure imgf000092_0001
MOM protected 36r (16 mg, 18.45 µmol) was dissolved in CH3CN (2 mL) and cooled to 0°C.3 drops of HBr (48% in H2O) were slowly added and then the mixture was stirred for 1 h at 0°C. The mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous NaHCO3 solution (5 mL). The aqueous phase was extracted with EtOAc (3x5 mL) and the organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was puri- fied by flash chromatography (CH2Cl2/MeOH 50:1) to give (4R)-Disorazole C1 31r (8 mg, 12.9, 10.33µmol, 56%) as a colorless wax. General Data: C44H58N2O10; FW: 774.41; TLC: Rf= 0.20 (CH2Cl2/MeOH 50:1); UV (+); Vanillin: dark green;
Figure imgf000093_0001
= -128.00 (c = 0.1, MeOH). 1H-NMR (600 MHz, CD3OD): δ (ppm): 8.23 (s, 2H, NC=CH); 6.51 (dd, J = 14.9, 11.3 Hz, 2H, CH(OCH3)CH=CH); 6.41 (app t, J = 11.2 Hz, 2H, CH2CH=CH); 6.29 (dd, J = 11.3, 11.1 Hz, 2H, CHCH=CHCH); 5.91 (dd, J = 11.3, 11.0 Hz, 2H, CHCH=CHCH); 5.64 (dq, J = 15.1, 6.3 Hz, 2H, CH3CH=CH); 5.57 (ddd, J = 15.4, 7.6, 1.5 Hz, 2H, CH3CH=CH); 5.53 (dd, J = 15.1, 8.3 Hz, 2H, CH(OCH3)CH=CH); 5.48 (app dt, J = 10.0, 6.7 Hz, 2H, CH2CH=CH); 5.29 (dd, J = 11.3, 2.1 Hz, 2H, CHOC=O); 4.13 (ddd, J = 7.9, 7.2, 5.1 Hz, 2H, CHOCH3); 3.91 (d, J = 7.3 Hz, 2H, CHOH); 3.21 (s, 6H, CHOCH3); 2.99 (dd, J = 15.5, 7.3 Hz, 2H, CH2CHOCH3); 2.75 (dd, J = 15.6, 5.0 Hz, 2H, CH2CHOCH3); 2.71 (ddd, J = 13.8, 10.9, 10.1 Hz, 2H, CH2CH=CH); 2.45 (dd, J = 13.1, 6.1 Hz, 2H, CH2CH=CH); 1.71 (dd, J = 6.1, 1.1 Hz, 6H, CH=CHCH3); 0.991 (s, 6H, CCH3); 0.953 (s, 6H, CCH3). 13C-NMR (151 MHz, CD3OD): δ (ppm): 164.13 (C=O); 162.25 (C=N); 145.79 (CH); 134.07 (C); 134.05 (CH); 131.49 (CH); 131.04 (CH); 129.98 (CH); 129.55 (CH); 129.20 (CH); 127.42 (CH); 126.89 (CH); 80.45 (CH); 79.19 (CH); 78.00 (CH); 56.82 (CH3); 42.74 (C); 36.02 (CH2); 29.16 (CH2); 19.71 (CH3); 19.69 (CH3); 18.02 (CH3). MS (ESI): m/z (%): 775.41 (100) [M+H]+, 792.44 (48) [M+NH4]+, 757.40 (11), 771.36 (8), 693.35 (4). HR-MS (ESI): calculated for C44H59N2O10 [M+H]+: 775.4170, found 775.4175, 792.4445 [M+NH4]+. The following Examples 53 to 63 disclose the synthesis of Bis(thiazolyl)-Diso- razole C1 (60t). Example 53: (R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynamide (21t)
Figure imgf000094_0001
Carboxylic acid 25 (2.3 g, 7.41 mmol, 1 eq) was dissolved in THF (40 mL), cooled to 0°C and ethyl chloroformate (0.917 mL, 9.63 mmol, 1.3 eq) was ad- ded dropwise, followed by NEt3 (1.44 mL, 10.37 mmol, 1.4 eq). The mixture was stirred for 30 min at 0°C and then 25% aqueous NH4OH solution (3 mL) was added. The mixture was stirred for 30 min at 0°C and 1h at room tempe- rature. The solution was washed with H2O (30 mL) and the aqueous phase was extracted with EtOAc (3x25 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude amide 50t as a yellow oil, which was used for the next step without further purification. General Data: C17H31NO2Si; FW: 309.21; TLC: Rf= 0.2 (Et2O); UV (+); Vanil- lin: brown;
Figure imgf000094_0003
= +24.4 (c = 0.75, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 6.01 (dd, J = 16.0, 7.4 Hz, 1H, CH=CH); 5.80 (dd, J = 15.9, 1.0 Hz, 1H, CH=CH); 4.06-4.01 (m, 1H, CHOCH3); 3.33 (s, 3H, OCH3); 2.49-2.44 (m, 2H, CH2CH); 1.07 (s, 21H, Si(CH(CH3))3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 173.4 (C=O); 141.4 (CH); 113.6 (CH); 104.1 (C); 93.0 (C); 78.3 (CH); 57.1 (CH3); 41.8 (CH2); 18.7 (CH3); 11.4 (CH). IR(neat): 2921 (s); 3339 (br); 2942 (s); 2865 (s); 2134 (w); 1667 (s); 1462 (m); 1385 (m); 1241 (w); 1093 (s); 996 (m); 957 (m); 882 (s); 662 (s) cm-1. MS (ESI): m/z (%): 278.19 (100), 332.20 (10) [M+Na]+., 619.43 (8), 310.22 (4) [M+H]+. HRMS (ESI) m/z: [M+H]+ Calcd for C17H32NO2Si: 310.2202; found: 310.2206. Example 53: (R,E)-3-methoxy-7-(triisopropylsilyl)hept-4-en-6-ynethioamide (51t)
Figure imgf000094_0002
51t Lawesson‘s reagent (2.1 g, 5.19 mmol, 0.7 eq) was added to a solution of crude 50t in THF (65 mL) and the mixture was stirred for 30 min at room temperature. The solution was washed with Brine (100 mL) and the aqueous phase was extracted with Et2O (3x70 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by flash chromatography (hexane/EtOAc 4:1) afforded 51t (1.76 g, 5.41 mmol, 73%) as an orange oil. General Data: C17H31NOSSi; FW: 325.19; TLC: Rf= 0.25 (pentane/Et2O 3:2); UV (+);
Figure imgf000095_0002
= +7.0 (c = 1.0, CHCl3). 1H-NMR (400 MHz, CDCl3): δ (ppm): 6.00 (dd, J = 15.9, 7.2 Hz, 1H, CH=CH); 5.81 (dd, J = 15.9, 0.9 Hz, 1H, CH=CH); 4.11-4.03 (m, 1H, CHOCH3); 3.34 (s, 3H, OCH3); 2.97 (dd, J = 15.1, 3.1 Hz, 1H, 1CH2CH); 2.87 (dd, J = 15.1, 8.1 Hz, 1H, 1CH2CH); 1.07 (s, 21H, Si(CH(CH3))3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 206.3 (C=S); 140.8 (CH); 113.9 (CH); 104.0 (C); 93.2 (C); 80.4 (CH); 57.2 (CH3); 50.4 (CH2); 18.7 (CH3); 11.4 (CH). IR(neat): 3658 (m); 3313 (m); 3173 (m); 2970 (s); 2865 (s); 2327 (w); 1626 (m); 1461 (m); 1384 (m); 1256 (m); 1073 (s); 951 (s); 882 (m); 664 (s) cm-1. MS (ESI): m/z (%): 294.17 (100), 112.02 (9), 638.42 (23), 326.19 (7) [M+H]+,250.10 (6). HRMS (ESI) m/z: [M+H]+ Calcd for C17H32NOSSi: 326.1974; found: 326.1943. Example 55: Methyl (R,E)-2-(2-methoxy-6-(triisopropylsilyl)hex-3-en-5-yn-1-yl)thia- zole-4-carboxylate (52t)
Figure imgf000095_0001
NaHCO3 (2.3 g, 27.05 mmol, 5 eq) was added portionwise to a solution of 51t (1.76 g, 5.41 mmol, 1 eq) in THF (45 mL) at 0°C, followed by a dropwise addition of methyl bromopyruvate (1.73 mL, 16.23 mmol, 3 eq). The mixture was stirred for 1h at 0°C, then the reaction was cooled to -30°C and pyridine (3.06 mL, 37.87 mmol, 7 eq) and TFAA (3 mL, 21.64 mmol, 4 eq) were sequentially added dropwise. The mixture was stirred for 1h at -30°C and then qunched with Brine (50 mL). The layers were separated and the aqueous phase was extracted with Et2O (3x40 mL). The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chroma- tography (hexane/EtOAc 5.1 to 4:1) to give thiazole 52t (1.83 g, 4.49 mmol, 83%) as a yellow oil. General Data: C21H33NO3SSi; FW: 407.20; TLC: Rf= 0.35 (pentane/Et2O 2:1); UV (+); Vanillin: brown;
Figure imgf000096_0002
= +1.76 (c = 0.85, CHCl3). 1H-NMR (400 MHz, CDCl3): δ (ppm): 8.11 (s, 1H, C=CH); 6.04 (dd, J = 16.0, 7.2 Hz, 1H,CH=CH); 5.78 (dd, J = 16.0, 0.9 Hz, 1H, CH=CH); 4.02-3.92 (m, 1H, CHOCH3); 3.97-3.88 (m, 1H, 1CH2CH); 3.95 (s, 3H, COOCH3); 3.31 (s, 3H, CHOCH3); 3.20 (dd, J = 15.0, 8.8 Hz, 1H, 1CH2CH); 1.08 (s, 21H, Si(CH(CH3))3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 167.8 (C=O); 162.0 (C=N); 145.9 (C); 141.6 (CH); 128.5 (CH); 113.7 (CH); 104.2 (C); 93.0 (C); 80.3 (CH); 57.1 (CH3); 52.6 (CH3); 39.5 (CH2); 18.7 (CH3); 11.4 (CH). IR(neat): 3118 (w); 2926 (m); 2325 (m); 2130 (w); 1725 (s); 1462 (m); 1324 (m); 1238 (s); 1093 (s); 995 (m); 883 (m); 754 (m); 675 (s) cm-1. MS (ESI): m/z (%): 376.18 (100), 408.21 (88) [M+H]+, 430.18 (22), 194.02 (6). HRMS (ESI) m/z: [M+H]+ Calcd for C21H34NO3SSi: 408.2029; found: 408.2067. Example 56: Methyl (R,E)-2-(2-methoxyhex-3-en-5-yn-1-yl)thiazole-4-carboxylate (53t)
Figure imgf000096_0001
TIPS thiazole 52t (1.4 g, 3.44 mmol, 1 eq) was carefully dried under high vac- uum, dissoved in THF (35 mL) and cooled to 0°C. TBAF (1 M in THF, 3.78 mL, 3.78 mmol, 1.1 eq) was added dropwise and the mixture was stirred for 30 min at room temperature and then quenched with water (30 mL). The aqueous phase was extracted with Et2O (3x20 mL) and the organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by flash chromatography (pentane/Et2O 2:1 to 1:1) afforded thiazole 53t (691 mg, 2.75 mmol, 80%) as a yellow oil. General Data: C12H13NO3S; FW: 251.06; TLC: Rf= 0.30 (pentane/Et2O 1:1); UV (+); Vanillin: brown; = +12.2 (c = 1.0, CHCl3
Figure imgf000097_0001
). 1H-NMR (400 MHz, CDCl3): δ (ppm): 8.11 (s, 1H, NC=CH); 6.12 (dd, J = 16.1, 7.1, 1H, CH=CH); 5.72 (ddd, J = 15.9, 2.1, 0.9 Hz, 1H, CH=CH); 4.04-3.96 (m, 1H, CHOCH3); 3.95 (s, 3H, COOCH3); 3.36-2.27 (m, 1H, 1CH2CH); 3.31 (s, 3H, CHOCH3); 3.21 (dd, J = 15.1, 8.5 Hz, 1H, 1CH2CH); 2.94 (d, J = 2.2 Hz, 1H, CCH). 13C-NMR (100 MHz, CDCl3): δ (ppm): 167.4 (C=O); 162.0 (C=N); 146.1 (C); 143.1 (CH); 128.5 (CH); 112.3 (CH); 81.1 (C); 80.1 (CH); 79.0 (CH); 57.1 (CH3); 52.6 (CH3); 39.4 (CH2). IR(neat): 3626 (w); 3219 (m); 3126 (m); 2953 (m); 2836 (w); 1719 (s); 1482 (s); 1319 (m); 1236 (s); 1194 (s); 1091 (s); 983 (s); 915 (m); 782 (m); 672 (m) cm-1. MS (ESI): m/z (%): 252.07 (100) [M+H]+, 220.04 (95), 274.05 (34) [M+Na]+, 206.03 (13), 194.03 (8). HRMS (ESI) m/z: [M+H]+ Calcd for C12H14NO3S: 252.0694; found: 252.0711. Example 57: Methyl 2-((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)- 11,11-dimethyl-10-((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)thi- azole-4-carboxylate (54t)
Figure imgf000098_0001
The vinyl iodide 17 (595 mg, 1.27 mmol, 1 eq) was dissolved in degassed CH3CN (12 mL) and CuI (57 mg, 0.381 mmol, 0.3 eq) and PdCl2(PPh3)2 (89 mg, 0.127 mmol, 0.1 eq) were added. The mixture was degassed by freeze- pump-thaw (2 cycles) and then cooled to -15°C (ice/acetone bath). NEt3 (1.06 mL, 7.62 mmol, 6 eq) was added, followed by a slow addition of the enyne 53t (383 mg, 1.52 mmol, 1.2 eq) in degassed CH3CN (3 mL). The solution became green and after 15 min the bath was removed. The mixture was stirred for 1 h at room temperature and quenched with saturated aqueous NH4Cl solution (15 mL). The aqueous phase was extracted with Et2O (3x10 mL) and the com- bined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (pentane/Et2O 2:1) to give the monomer 54t (563 mg, 0.952 mmol, 75%) as a yellow oil. General Data: C31H49NO6SSi; FW: 591.31; TLC: Rf= 0.20 (pentane/Et2O 2:1); UV (+); Vanillin: black;
Figure imgf000098_0002
= -8.5 (c = 0.85, CHCl3). 1H-NMR (600 MHz, CD3OD): δ (ppm): 8.29 (s, 1H, NC=CH); 6.11-6.04 (m, 1H, CH2CH=CH); 6.03-5.94 (m, 2H, CH=CH); 5.71-5.60 (m, 2H, CH(OCH3)CH=CH, CH=CHCH3); 5.40-5.33 (m, 1H, CH=CHCH3); 4.65 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.46 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.11-4.06 (m, 1H, CHOCH3); 3.91 (s, 3H, COOCH3); 3.89 (d, J = 9.2 Hz, 1H, CH2CHOTES); 3.71 (dd, J = 7.2, 3.8 Hz, 1H, CH2CHOTES); 3.34 (s, 3H, CHOCH3); 3.32 (s, 3H, CHOCH2OCH3); 3.26 (dd, J = 14.5, 4.6 Hz, 2H, CH2CHOCH3); 2.63-2.56 (m, 1H, 1CH2CH=CH); 2.46-2.38 (m, 1H, 1CH2CH=CH); 1.72 (dd, J = 6.6, 1.7 Hz, 3H, CH=CHCH3); 0.984 (app t, J = 7.9 Hz, 9H, OSi(CH2CH3)3); 0.934 (s, 3H, CCH3); 0.871 (s, 3H, CCH3); 0.638 (q, J = 8.0 Hz, 6H, OSi(CH2CH3)3). 13C-NMR (151 MHz, CD3OD): δ (ppm): 169.7 (C=O); 163.0 (C=N); 146.6 (C); 143.6 (CH); 141.7 (CH); 132.3 (CH); 129.9 (CH); 129.2 (CH); 114.7 (CH); 110.8 (CH); 94.5 (CH2); 92.5 (C); 88.9 (C); 82.7 (CH); 81.3 (CH); 77.9 (CH); 57.1 (CH3); 55.9 (CH3); 52.7 (CH3); 44.2 (C); 39.8 (CH2); 35.5 (CH2); 20.4 (CH3); 19.9 (CH3); 18.0 (CH3); 7.5 (CH3); 6.5 (CH2). IR(neat): 3120 (w); 2953 (m); 2877 (m); 1724 (m); 1464 (m); 1325 (m); 1238 (m); 1210 (m); 1089 (s); 1036 (s); 957 (m); 919 (m); 739 (s) cm-1. MS (ESI): m/z (%): 530.28 (100), 434.18 (97), 614.29 (22), 366.15 (16), 498.25 (18), 592.31 (<1) [M+H]+. HRMS (ESI) m/z: [M+H]+ Calcd for C31H50NO6SSi: 592.3128; found: 592.3130. Example 58: Methyl 2-((2R,3E,7Z,10S,12S,13E)-10-hydroxy-2-methoxy-12-(methoxy- methoxy)-11,11-dimethylpentadeca-3,7,13-trien-5-yn-1-yl)thiazole-4-car- boxylate (55t)
Figure imgf000099_0001
CSA (18 mg, 0.0744 mmol, 0.2 eq) was added at 0°C to a solution of TES protected monomer 54t (220 mg, 0.372 mmol, 1 eq) in CH2Cl2 (9 mL) and MeOH (9 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Saturated aqueous NaHCO3 solution (20 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3x15 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Et2O/pentane 2:1) giving deprotected monomer 55t (168 mg, 0.353 mmol, 95%) as a slightly yellow oil. General Data: C25H35NO6S; FW: 477.22; TLC: Rf= 0.25 (Et2O/Pentane 2:1); UV (+); Vanillin: black;
Figure imgf000100_0001
= -18.0 (c = 1.8, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.10 (s, 1H, NC=CH); 6.22-6.16 (m, 1H, CH2CH=CH); 5.96 (dd, J = 15.9, 7.1 Hz, 1H, CCH=CHCH); 5.87 (dd, J = 15.8, 1.8 Hz, 1H, CCH=CHCH2); 5.70-5.62 (m, 2H, CH(OCH3)CH=CH, CH=CHCH3); 5.42-5.35 (m, 1H, CH=CHCH3); 4.65 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.47 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.02-3.95 (m, 1H, CHOCH3); 3.93 (s, 3H, COOCH3); 3.90 (d, J = 8.7 Hz, 1H, CH2CHOH); 3.67 (dd, J = 10.2, 2.5 Hz, 1H, CHOCH2OCH3); 3.37 (s, 3H, CHOCH3); 3.32-3.27 (m, 1H, 1CH2CHOCH3); 3.29 (s, 3H, CHOCH2OCH3); 3.21 (dd, J = 15.1, 8.7 Hz, 1H, 1CH2CHOCH3); 2.59-2.51 (m, 1H, 1CH2CH=CH); 2.37-2.28 (m, 1H, 1CH2CH=CH); 1.74 (dd, J = 6.5, 1.6 Hz, 3H, CH=CHCH3); 0.913 (s, 3H, CCH3); 0.863 (s, 3H, CCH3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 167.6 (C=O); 162.0 (C=N); 146.0 (C); 143.2 (CH); 140.2 (CH); 132.0 (CH); 128.4 (CH); 126.9 (CH); 113.8 (CH); 109.8 (CH); 93.8 (CH2); 91.2 (C); 88.3 (C); 84.7 (CH); 80.4 (CH); 76.1 (CH); 56.9 (CH3); 56.2 (CH3); 52.5 (CH3); 41.0 (C); 39.6 (CH2); 32.8 (CH2); 21.1 (CH3); 19.7 (CH3); 18.0 (CH3). IR(neat): 3657 (w); 3452 (br); 2972 (s); 2888 (m); 2326 (w); 1722 (s); 1603 (m); 1440 (m); 1339 (m); 1256 (m); 1146 (m); 1091 (s); 1033 (s); 954 (s); 922 (m); 753 (m) cm-1. MS (ESI): m/z (%): 320.10 (100), 384.16 (56), 416.19 (52), 446.20 (45), 228.07 (29), 500.20 (22), 478.23 (12) [M+H]+. HRMS (ESI) m/z: [M+H]+ Calcd for C25H36NO6S: 478.2263; found: 478.2257. Example 59: 2-((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)-11,11-dime- thyl-10- ((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)thiazole-4- carboxylic acid (56t)
Figure imgf000101_0001
LiOH (1 M in H2O, 0.777 mL, 0.777 mmol, 3 eq) was added to a solution of 54t (153 mg, 0.259 mmol, 1 eq) in THF (3.5 mL). The mixture was stirred for 3 h at room temperature and neutralized with 1 M HCl (2 mL). The aqueous phase was extracted with Et2O (3x3 mL) and the organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give acid 56t (148 mg, 0.256 mmol, 99%) as a yellow oil, which was used for the next step without further purification. General Data: C30H47NO6SSi; FW: 577.29; TLC: UV (+); Vanillin: black;
Figure imgf000101_0002
= +36.9 (c = 0.55, CHCl3). 1H-NMR (600 MHz, CDCl3): δ (ppm): 8.25 (s, 1H, NC=CH); 6.11-6.04 (m, 1H, CH2CH=CH); 6.03-5.94 (m, 2H, CCH=CHCH); 5.72-5.60 (m, 2H, CH(OCH3)CH=CH, CH=CHCH3); 5.40-5.33 (m, 1H, CH=CHCH3); 4.65 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.46 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.13-4.04 (m, 1H, CHOCH3); 3.92-3.87 (m, 1H, CHOTES); 3.71 (dd, J = 7.2, 3.7 Hz, 1H, CHOCH2OCH3); 3.34 (s, 3H, CHOCH3); 3.32 (s, 3H, CHOCH2OCH3); 3.26 (dd, J = 13.7, 4.6 Hz, 2H, CH2CHOCH3); 2.63-2.56 (m, 1H, 1CH2CH=CH); 2.46- 2.38 (m, 1H, 1CH2CH=CH); 1.72 (dd, J = 6.4, 1.6 Hz, 3H, CH=CHCH3); 1.01-0.959 (m, 9H, OSi(CH2CH3)3); 0.937 (s, 3H, CCH3); 0.873 (s, 3H, CCH3); 0.638 (q, J = 8.0 Hz, 6H, OSi(CH2CH3)3). 13C-NMR (151 MHz, CDCl3): δ (ppm): 164.4 (C=O); 162.8 (C=N); 145.0 (CH); 143.2 (CH); 140.2 (CH); 133.0 (C); 131.1 (CH); 127.9 (CH); 114.0 (CH); 109.5 (CH); 93.6 (CH2); 91.2 (C); 88.5 (C); 81.8 (CH); 79.3 (CH); 76.5 (CH); 56.9 (CH3); 55.7 (CH3); 43.2 (C); 34.4 (CH2); 30.5 (CH2); 19.8 (CH3); 19.4 (CH3); 18.0 (CH3); 7.3 (CH3); 5.7 (CH2). IR(neat): 3495 (w); 2952 (m); 2877 (m); 1715 (m); 1468 (m); 1415 (w); 1192 (m); 1091 (s); 1033 (s); 956 (m); 921 (m); 825 (m); 723 (s); 542 (w) cm-1. MS (ESI): m/z (%): 420.17 (100), 516.26 (77), 600.28 (49), 546.27 (24), 388.14 (17), 352.14 (8), 306.08 (4), 578.27 (<1) [M+H]+. HRMS (ESI) m/z: [M+H]+ Calcd for C30H48NO6SSi: 578.2972; found: 578.2963. Example 60: (2E,4S,6S,8Z,12E,14R)-14-methoxy-15-(4-(methoxycarbonyl)thiazol-2-yl)- 4- (methoxymethoxy)-5,5-dimethylpentadeca-2,8,12-trien-10-yn-6-yl 2- ((2R,3E,7Z,10S,12S,13E)-2-methoxy-12-(methoxymethoxy)-11,11-dime- thyl-10-((triethylsilyl)oxy)pentadeca-3,7,13-trien-5-yn-1-yl)thiazole-4-car- boxylate (57t)
Figure imgf000102_0001
The crude acid 56t (140 mg, 0.243 mmol, 1.2 eq) was dissolved in THF (4 mL) and treated at room temperature with NEt3 (0.175 mL, 1.25 mmol, 6 eq) and 2,4,6-trichlorobenzoyl chloride (0.130 mL, 0.836 mmol, 4 eq). The turbid solu- tion was stirred for 2 h at room temperature and then diluted with toluene (2 mL) and added dropwise to a solution of alcohol 55t (100 mg, 0.209 mmol, 1 eq) and DMAP (153 mg, 1.25 mmol, 6 eq) in toluene (5 mL). The mixture was stirred overnight at room temperature and then quenched with saturated aque- ous NH4Cl solution (20 mL). The aqueous phase was extracted with EtOAc (3x15 mL) and the organic layers were dried over Na2SO4, filtered and con- centrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 2:1) to afford 57t (168 mg, 0.162 mmol, 77%) as a slightly yellow oil. General Data: C55H80N2O11S2Si; FW: 1036.50; TLC: Rf = 0.45 (hexane/EtOAc 1:1); UV (+); Vanillin: black; 0
Figure imgf000103_0001
= +26.7 (c = 1.25, CHCl3). 1H-NMR (400 MHz, CD3OD): δ (ppm): 8.30 (s, 1H, NC=CH); 8.23 (s, 1H, NC=CH); 6.12-6.03 (m, 2H, CH=CH); 6.025.92 (m, 4H, CH=CH); 5.76-5.55 (m, 4H, CH=CH); 5.48-5.31 (m, 2H, CH=CH); 5.24 (app dd, J = 6.7, 6.0 Hz, 1H, CHOC=O); 4.64 (dd, J = 8.9, 6.5 Hz, 2H, OCH2OCH3); 4.46 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.40 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.14-4.06 (m, 2H, CHOCH3); 3.91-3.87 (m, 1H, CHOCH2OCH3);3.90 (s, 3H, COOCH3); 3.83 (d, J = 9.0 Hz, 1H, CHOCH2OCH3); 3.71 (dd, J = 7.0, 3.7 Hz, 1H, CH2CHOTES); 3.34 (s, 3H, CHOCH3); 3.33 (s, 3H, CHOCH3); 3.32 (s, 3H, CHOCH2OCH3); 3.29 (s, 3H, CHOCH2OCH3); 3.28-3.23 (m, 4H, CH2CHOCH3); 2.73 (app dd, J = 6.9, 7.2 Hz, 2H, CH2CH=CH); 2.65-2.55 (m, 1H, 1CH2CH=CH); 2.47-2.37 (m, 1H, 1CH2CH=CH); 1.712 (app d, J = 6.2 Hz, 6H, CH=CHCH3); 1.06 (s, 3H, CCH3); 1.01 (s, 3H, CCH3); 0.982 (app t, J = 7.8 Hz, 9H, OSi(CH2CH3)3); 0.935 (s, 3H, CCH3); 0.871 (s, 3H, CCH3); 0.637 (q, J = 8.0 Hz, 6H, OSi(CH2CH3)3). 13C-NMR (100 MHz, CD3OD): δ (ppm): 169.6 (C=O); 169.5 (C=O); 163.0 (C=N); 162.2 (C=N); 147.1 (CH); 146.6 (CH); 143.6 (CH); 141.9 (CH); 141.8 (CH); 141.2 (C); 133.1 (C); 132.3 (CH); 130.0 (CH); 129.8 (CH); 129.2 (CH); 128.5 (CH); 114.7 (CH); 114.6 (CH); 112.1 (CH); 110.8 (CH); 94.6 (CH2); 94.5 (CH2); 92.6 (C); 92.5 (C); 88.9 (C); 88.5 (C); 82.8 (CH); 82.7 (CH); 81.4 (CH); 81.2 (CH); 78.6 (CH); 77.9 (CH); 57.1 (CH3); 57.0 (CH3); 56.3 (CH3); 56.0 (CH3); 52.7 (CH3); 44.2 (C); 42.8 (C); 39.8 (CH2); 39.7 (CH2); 35.5 (CH2); 32.4 (CH2); 20.4 (CH3); 20.3 (CH3); 19.9 (CH3); 19.7 (CH3); 18.1 (CH3); 18.0 (CH3); 7.5 (CH3); 6.5 (CH2). IR(neat): 2952 (m); 2879 (m); 2224 (w); 1736 (s); 1468 (m); 1371 (m); 1238 (s); 1206 (s); 1091 (s); 1033 (s); 956 (s); 918 (m); 736 (s) cm-1. MS (ESI): m/z (%): 1005.55 (100) [M+H]+, 1022.56 (760) [M+NH4]+, 943.52 (45), 973.53 (28), 847.43 (8). HRMS (ESI) m/z: [M+H]+ Calcd for C55H81N2O11S2Si: 1036.4973; found: 1036.4981. Example 61: Bis(thiazolyl)-(16,16’)-bis(methoxymethyl)-(9,10,9’,10’)-tetradehydrido- disorazole C1 (58t)
Figure imgf000104_0001
CSA (8 mg, 0.0324 mmol, 0.2 eq) was added at 0°C to a solution TES pro- tected dimer 57t (168 mg, 0.162 mmol, 1 eq) in CH2Cl2 (8 mL) and MeOH (8 mL). The mixture was stirred for 1 h at 0°C under normal atmosphere. Satu- rated NaHCO3 solution (20 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3x15 mL) and the combined or- ganic extracts were dried over Na2SO4, filtered and concentrated in vacuo giv- ing the deprotected alcohol as a slightly yellow oil, which was used in the next step without further purification. General Data: C49H66N2O11S2; FW: 922.41; TLC: Rf= 0.30 (CH2Cl2/MeOH 50:1); UV (+); Vanillin: black;
Figure imgf000104_0002
= +36.9 (c = 0.55, CHCl3). 1H-NMR (400 MHz, CDCl3): δ (ppm): 8.11 (s, 1H, NC=CH); 7.99 (s, 1H, NC=CH); 6.27-6.12 (m, 1H, CH2CH=CH); 6.05-6.93 (m, 3H, CH=CH); 5.89 (ddd, J = 16.0, 4.8, 2.5 Hz, 2H, CH=CH); 5.73-5.61 (m, 3H, CH=CH); 5.56 (d, J = 10.3 Hz, 1H, CH=CH); 5.45-5.33 (m, 2H, CH=CH); 5.28 (dd, J = 8.0, 4.8 Hz, 1H, CHOC=O); 4.66 (d, J = 6.6 Hz, 2H, 1OCH2OCH3); 4.48 (d, J = 6.7 Hz, 1H, 1OCH2OCH3); 4.40 (d, J = 6.7 Hz, 1H, CHOCH2OCH3); .4.06-3.96 (m, 2H, CHOCH3); 3.94 (s, 3H, COOCH3); 3.92 (m, 1H, CHOCH2OCH3); 3.79 (d, J = 9.0 Hz, 1H, CHOCH2OCH3); 3.69 (dd, J = 10.1, 2.2 Hz, 1H, CHOH); 3.38 (s, 3H, CHOCH3); 3.32 (s, 3H, CHOCH3); 3.31 (s, 3H, CHOCH2OCH3); 3.35-2.29 (m, 2H, CH2CHOCH3); 23.30 (s, 3H, CHOCH2OCH3); 3.26-2.18 (m, 2H, CH2CHOCH3); 2.80-2.66 (m, 2H, CH2CH=CH); 2.61-2.50 (m, 1H, 1CH2CH=CH); 2.40-2.28 (m, 1H, 1CH2CH=CH); 1.75 (dd, J = 6.3, 1.3 Hz, 3H, CH=CHCH3); 1.71 (dd, J = 6.5, 1.6 Hz, 3H, CH=CHCH3); 1.05 (s, 3H, CCH3); 1.00 (s, 3H, CCH3); 0.927 (s, 3H, CCH3); 0.878 (s, 3H, CCH3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 167.5 (C=O); 167.4 (C=O); 162.1 (C=N); 160.9 (C=N); 146.6 (CH); 146.1 (CH); 143.2 (CH); 140.5 (CH); 140.4 (CH); 132.0 (CH); 131.9 (CH); 128.5 (CH); 127.6 (C); 127.3 (C); 126.9 (CH); 125.7 (CH); 113.7 (CH); 113.6 (CH); 111.1 (CH); 109.8 (CH); 93.8 (CH2); 93.7 (CH2); 91.5 (C); 91.3 (C); 88.3 (C); 88.1 (C); 84.7 (CH); 81.6 (CH); 80.4 (CH); 80.4 (CH); 77.4 (CH); 76.2 (CH); 57.0 (CH3); 56.9 (CH3); 56.2 (CH3); 56.1 (CH3); 52.6 (CH3); 41.9 (C); 41.0 (C); 39.7 (CH2); 32.9 (CH2); 31.6 (CH2); 30.4 (CH2); 21.1 (CH3); 20.0 (CH3); 19.8 (CH3); 19.6 (CH3); 18.1 (CH3); 18.0 (CH3). IR(neat): 3500 (br); 2934 (m); 2886 (m); 1723 (m); 1468 (m); 1345 (m); 1205 (s); 1092 (s); 1032 (s); 971 (s); 919 (m); 749 (m); 540 (w) cm-1. MS (ESI): m/z (%): 923.42 (100) [M+H]+, 891.39 (10), 945.40 (6) [M+Na]+, 765.29 (5). HRMS (ESI) m/z: [M+H]+ Calcd for C49H67N2O11S2: 923.4186; found: 923.4194. The crude deprotected alcohol was dissolved in THF (6 mL) and treated at room temperature with LiOH (1 M in H2O, 0.486 mL, 0.486 mmol, 3 eq). The mixture was stirred overnight at room temperature and neutralized with 1 M HCl (2 mL). The aqueous phase was extracted with Et2O (3x3 mL) and the organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the seco-acid as a yellow wax, which was used without further purification. General Data: C48H64N2O11S2; FW: 908.40; TLC: UV (+); Vanillin: grey;
Figure imgf000105_0001
= +28.5 (c = 1.0, CHCl3). 1H-NMR (400 MHz, CDCl3): δ (ppm): 8.18 (s, 1H, NC=CH); 8.00 (s, 1H, NC=CH); 6.26-6.14 (m, 1H, CH2CH=CH); 6.03-5.93 (m, 3H, CH=CH); 5.93- 5.83 (m, 2H, CH=CH); 5.71-5.61 (m, 3H, CH=CH); 5.56 (d, J = 10.1 Hz, 1H, CH=CH); 5.44-5.33 (m, 2H, CH=CH); 5.28 (dd, J = 7.5, 5.8 Hz, 1H, CHOC=O); 4.67 (d, J = 6.6 Hz, 2H, OCH2OCH3); 4.48 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.41 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.08-3.97 (m, 2H, CHOCH3); 3.91 (d, J = 8.6 Hz, 1H, CHOCH2OCH3); 3.79 (d, J = 9.0 Hz, 1H, CHOCH2OCH3); 3.70 (dd, J = 10.2, 2.0 Hz, 1H, CHOH); 3.39 (s, 3H, CHOCH3); 3.35-3.28 (m, 2H, CH2CHOCH3); 3.33 (s, 3H, CHOCH3); 3.32 (s, 3H, CHOCH2OCH3); 3.31 (s, 3H, CHOCH2OCH3); 3.27-3.16 (m, 2H, CH2CHOCH3); 2.76-2.66 (m, 2H, CH2CH=CH); 2.60-2.50 (m, 1H, 1CH2CH=CH); 2.41-2.30 (m, 1H, 1CH2CH=CH); 1.75 (d, J = 6.3 Hz, 3H, CH=CHCH3); 1.71 (d, J = 6.3, 1.4 Hz, 3H, CH=CHCH3); 1.05 (s, 3H, CCH3); 0.999 (s, 3H, CCH3); 0.928 (s, 3H, CCH3); 0.879 (s, 3H, CCH3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 167.6 (C=O); 167.5 (C=O); 163.2 (C=N); 160.8 (C=N); 146.4 (CH); 145.8 (CH); 143.1 (CH); 140.6 (CH); 140.4 (C); 132.1 (CH); 129.2 (C); 129.1 (CH); 127.8 (CH); 127.2 (CH); 126.8 (CH); 125.6 (CH); 113.7 (CH); 111.0 (CH); 109.9 (CH); 109.8 (CH); 93.8 (CH3); 93.6 (CH3); 91.5 (C); 91.3 (C); 88.3 (C); 88.1 (C); 84.7 (CH); 81.6 (CH); 80.4 (CH); 80.2 (CH); 77.4 (CH); 76.3 (CH); 57.0 (CH3); 56.9 (CH3); 56.2 (CH3); 56.1 (CH3); 41.9 (C); 41.0 (C); 32.8 (CH2); 31.6 (CH2); 30.5 (CH2); 29.8 (CH2); 21.1 (CH3); 20.0 (CH3); 19.8 (CH3); 19.5 (CH3); 18.1 (CH3); 18.0 (CH3). IR(neat): 3507 (br); 2924 (m); 2826 (w); 1722 (s); 1469 (m); 1337 (m); 1200 (s); 1146 (m); 1093 (s); 1030 (s); 956 (s); 911 (s); 730 (s); 576 (w) cm-1. MS (ESI): m/z (%): 909.40 (100) [M+H]+, 931.39 (18) [M+Na]+, 897.40 (12), 847.36 (9). HRMS (ESI) m/z: [M+H]+ Calcd for C48H65N2O11S2: 909.4030; found: 909.4003. The crude seco-acid was dissolved in THF (10 mL) and treated at room tem- perature with NEt3 (506 µL, 3.24 mmol, 20 eq) and 2,4,6-trichlorobenzoyl chlo- ride (225 µL, 1.62 mmol, 10 eq). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (3 mL) and added dropwise to a so- lution of DMAP (791 mg, 6.48 mmol, 40 eq) in toluene (80 mL). The mixture was stirred overnight at room temperature and then quenched with saturated aqueous NH4Cl solution (20 mL) and water (20 mL) and the aqueous phase was extracted with EtOAc (3x40 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Et2O/pentane 2:1 to 1:1) to afford the macrocycle 58t (65 mg, 0.0729 mmol, 45% from 57t) as a slightly yellow wax. General Data: C48H62N2O10S2; FW: 890.38; TLC: Rf= 0.50 (CH2Cl2/MeOH 50:1); UV (+); Vanillin: black;
Figure imgf000106_0001
= +98.2 (c = 0.5, CHCl3). 1H-NMR (400 MHz, CDCl3): δ (ppm): 7.98 (s, 2H, NC=CH); 6.02-5.90 (m, 4H, CH=CH); 5.79 (dd, J = 15.8, 2.0 Hz, 2H, CH=CH); 5.66 (dd, J = 15.4, 6.5 Hz, 2H, CH=CH); 5.54 (d, J = 10.8 Hz, 2H, CH=CH); 5.46-5.37 (m, 2H, CH=CH); 5.32 (dd, J = 10.6, 2.8 Hz, 2H, CHOC=O); 4.67 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.42 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.15-4.07 (m, 2H, CHOCH3); 3.77 (d, J = 8.9 Hz, 2H, CHOCH2OCH3); 3.53-3.46 (m, 2H, CH2CH=CH); 3.37 (s, 6H, CHOCH3); 3.34 (s, 6H, CHOCH2OCH3); 3.31-3.22 (m, 2H, CH2CH=CH); 3.05- 2.90 (m, 2H, CH2CHOCH3); 2.50-2.41 (m, 2H, CH2CH=CH); 1.73 (dd, J = 6.4, 1.4 Hz, 6H, CH=CHCH3); 1.07 (s, 6H, CCH3); 1.03 (s, 6H, CCH3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 165.8 (C=O); 160.6 (C=N); 147.0 (CH); 140.5 (CH); 140.4 (CH); 131.9 (C); 128.4 (CH); 127.4 (CH); 114.5 (CH); 112.1 (CH); 93.8 (CH2); 91.2 (C); 88.2 (C); 81.7 (CH); 79.9 (CH); 77.4 (CH); 56.9 (CH3); 56.2 (CH3); 41.7 (C); 39.1 (CH2); 30.5 (CH2); 20.1 (CH3); 19.8 (CH3); 18.1 (CH3). IR(neat): 3115 (w); 2925 (m); 2854 (m); 1730 (m); 1468 (m); 1368 (m); 1236 (s); 1192 (s); 1092 (s); 1031 (s); 960 (s); 921 (m); 824 (m); 747 (m) cm-1. MS (ESI): m/z (%): 891.39 (100) [M+H]+, 829.35 (15), 913.37 (12) [M+Na]+, 879.39 (9). HRMS (ESI) m/z: [M+H]+ Calcd for C48H63N2O10S2: 891.3924; found: 891.3915. Example 62: Bis(thiazolyl)-(16,16’)-bis(methoxymethyl)-disorazole C1 (59t)
Figure imgf000107_0001
Nitrogen was bubbled for 15 min through a suspension of Zinc (6 g, 91.77 mmol) in H2O (30 mL) and then Cu(OAc)2·H2O (600 mg, 3.00 mmol) was added at room temperature and after 15 min AgNO3 (600 mg, 3.53 mmol) was added (exothermic reaction). The mixture was stirred for 30 min at room temperature, filtered by suction and washed with H2O (40 mL), MeOH (30 mL), acetone (30 mL) and Et2O (30 mL). This activated zinc solids were added to a solution of 58t (50 mg, 0.0562 mmol) in MeOH/H2O 1:1 (25 mL). The mixture was stirred for 24 h at 50°C, then filtered on a pad of silica with MeOH washes. The filtrate was concentrated in vacuo and the residue was purified by flash chromatog- raphy (CH2Cl2/MeOH 70:1) to afford 59t (30 mg, 0.0335, 60%) as a colorless wax. General Data: C48H66N2O10S2; FW: 894.42; TLC: Rf= 0.40 (CH2Cl2/MeOH 50:1); UV (+); Vanillin: dark green; = -52.8 (c = 0.5, CHCl3
Figure imgf000108_0001
). 1H-NMR (400 MHz, CDCl3): δ (ppm): 7.82 (s, 2H, NC=CH); 6.43 (dd, J = 15.3, 11.6 Hz, 2H, CH(OCH3)CH=CH); 6.33 (app t, J = 11.3 Hz, 2H, CH2CH=CH); 6.19 (dd, J = 11.7, 11.0 Hz, 2H, CHCH=CHCH); 5.89 (dd, J = 11.2, 10.9 Hz, 2H, CHCH=CHCH); 5.63 (dd, J = 15.3, 6.5 Hz, 2H, CH3CH=CH); 5.50 (dd, J = 15.1, 8.7 Hz, 2H, CH3CH=CH); 5.40 (ddd, J = 15.2, 9.0, 1.5 Hz, 2H, CH(OCH3)CH=CH); 5.31 (dd, J = 11.2, 2.5 Hz, 2H, CHOC=O); 5.26 (dd, J = 11.2, 2.2 Hz, 2H, CH2CH=CH); 4.66 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.39 (d, J = 6.6 Hz, 1H, 1OCH2OCH3); 4.10 (ddd, J = 12.8, 7.0, 5.0 Hz, 2H, CHOCH3); 3.74 (d, J = 9.0 Hz, 2H, CHOH); 3.43 (dd, J = 14.2, 5.3 Hz, 2H, CH2CHOCH3); 3.33 (s, 6H, CHOCH2OCH3); 3.28 (s, 6H, CHOCH3); 3.01 (dd, J = 14.2, 8.0 Hz, 2H, CH2CHOCH3); 2.65-2.55 (m, 2H, CH2CH=CH); 2.50 (dd, J = 15.3, 6.1 Hz, 2H, CH2CH=CH); 1.72 (d, J = 6.1 Hz, 3H, CH=CHCH3); 1.03 (s, 6H, CCH3); 0.979 (s, 6H, CCH3). 13C-NMR (100 MHz, CDCl3): δ (ppm): 166.6 (C=O); 160.8 (C=N); 147.1 (CH); 132.9 (C); 132.0 (CH); 129.9 (CH); 128.1 (CH); 127.2 (CH); 126.8 (CH); 125.7 (CH); 125.6 (CH); 125.5 (CH); 93.6 (CH2); 81.9 (CH); 81.2 (CH); 77.4 (CH); 56.6 (CH3); 56.1 (CH3); 41.8 (C); 30.5 (CH2); 29.8 (CH2); 20.3 (CH3); 19.9 (CH3); 18.1 (CH3). IR(neat): 2923 (s); 2853 (m); 1731 (m); 1466 (m); 1365 (w); 1194 (m); 1092 (s); 1032 (s); 973 (m); 920 (m); 731 (m) cm-1. MS (ESI): m/z (%): 895.42 (100) [M+H]+, 917.40 (12) [M+Na]+, 863.39 (5), 833.38 (4). HRMS (ESI) m/z: [M+H]+ Calcd for C48H67N2O10S2: 895.4237; found 895.4210. Example 63: Bis(thiazolyl)-Disorazole C1 (60t)
Figure imgf000109_0001
MOM protected 59t (12 mg, 13.4 µmol) was dissolved in CH3CN (1.5 mL) and cooled to 0°C. 2 drops of HBr (48% in H2O) were slowly added and then the mixture was stirred for 1 h at 0°C. The mixture was diluted with EtOAc (4 mL) and washed with saturated aqueous NaHCO3 solution (3 mL). The aqueous phase was extracted with EtOAc (3x5 mL) and the organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH 50:1) to give Bis(thiazolyl)-disorazole C 160t (6 mg, 7.44 µmol, 56%) as a colorless wax. General Data: C44H58N2O8S2; FW: 806.36; TLC: Rf= 0.20 (CH2Cl2/MeOH 50:1); UV (+); Vanillin: dark green; = -113.33 (c = 0.15, MeOH). 1
Figure imgf000109_0002
H-NMR (600 MHz, CD3OD): δ (ppm): 8.11 (s, 2H, NC=CH); 6.49 (dd, J = 15.2, 11.4 Hz, 2H, CH(OCH3)CH=CH); 6.39 (app t, J = 11.1 Hz, 2H, CH2CH=CH); 6.27 (dd, J = 11.2, 11.0 Hz, 2H, CHCH=CHCH); 5.85 (dd, J = 11.2, 11.1 Hz, 2H, CHCH=CHCH); 5.67 (dq, J = 15.3, 6.4 Hz, 2H, CH3CH=CH); 5.59 (ddd, J = 15.3, 7.9, 1.5 Hz, 2H, CH3CH=CH); 5.51 (dd, J = 15.4, 8.0 Hz, 4H, CH(OCH3)CH=CH); 5.26 (dd, J = 11.1, 2.2 Hz, 2H, CHOC=O); 4.13 (ddd, J = 7.9, 7.2, 5.3 Hz, 2H, CHOCH3); 3.86 (d, J = 7.9 Hz, 2H, CHOH); 3.25 (s, 6H, CHOCH3); 3.20 (dd, J = 12.4, 7.3 Hz, 2H, CH2CHOCH3); 3.01 (dd, J = 14.9, 5.6 Hz, 2H, CH2CHOCH3); 2.69 (ddd, J = 13.8, 10.9, 10.2 Hz, 2H, CH2CH=CH); 2.46 (dd, J = 14.1, 6.5 Hz, 2H, CH2CH=CH); 1.69 (dd, J = 6.1, 1.1 Hz, 6H, CH=CHCH3); 1.03 (s, 6H, CCH3); 0.972 (s, 6H, CCH3). 13C-NMR (151 MHz, CD3OD): δ (ppm): 169.0 (C=O); 162.3 (C=N); 147.5 (CH); 133.9 (C); 131.7 (CH); 130.6 (CH); 130.1 (CH); 129.7 (CH); 129.3 (CH); 129.0 (CH); 127.2 (CH); 126.6 (CH); 81.8 (CH); 79.2 (CH); 77.9 (CH); 56.9 (CH3); 42.8 (C); 40.5 (CH2); 29.2 (CH2); 19.5 (CH3); 19.4 (CH3); 18.0 (CH3). IR(neat): 3419 (br); 2924 (m); 2854 (m); 1723 (m); 1583 (m); 1447 (w); 1367 (w); 1312 (w); 1261 (w); 1101 (s); 1010 (m); 803 (m); 758 (m); 729 (m) cm-1. MS (ESI): m/z (%): 807.37 (100) [M+H]+, 829.35 (34) [M+Na]+, 172.13 (33); 155.11 (28), 659.52 (14), 798.36 (13). HRMS (ESI) m/z: [M+H]+ Calcd for C44H59N2O8S2: 807.3713; found 807.3704.

Claims

Claims 1. Compound of the formula III
Figure imgf000111_0001
III wherein: X is O, S, or NR; R is H, or alkyl(c≤8); R1 is H, alkyl(c≤8), or cycloalkyl(c≤8); R2 and R3 are each independently H, alkyl(c≤8), (CH2)n (n = 1-5); R4 is independently H, alkyl(c≤8), cycloalkyl(c≤8), alkenyl(c≤8), alkinyl(c≤8), allyl, propargyl, phenyl, or benzyl; Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyrrolyl, thiophenyl, pyridyl, or phenyl; * indicate the stereoisomeric centers of the compound; as well as the individual stereoisomers of this compound and/or a pharmaceutically acceptable salt thereof. 2. Compound of the Formula III according to claim 1, namely (4R)-Disorazole C1 of formula 31r
Figure imgf000112_0001
Bis(thiazolyl)-Disorazole C1 of formula 60t 3. Method for the production of a compound of formula III according to claim 1
Figure imgf000113_0001
(III) wherein: X is O, S, or NR; R is H, or alkyl(c≤8); R1 is H, alkyl(c≤8), or cycloalkyl(c≤8); R2 and R3 are each independently H, alkyl(c≤8), (CH2)n (n = 1-5); R4 is independently H, alkyl(c≤8), cycloalkyl(c≤8), alkenyl(c≤8), al- kinyl(c≤8), allyl, propargyl, phenyl, or benzyl; Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyr- rolyl, thiophenyl, pyridyl, or phenyl; * indicate the stereoisomeric centers of the compound; comprising the following steps: (a) reacting a compound of formula I
Figure imgf000113_0002
wherein R and R1 is as defined above; with a compound of formula II
Figure imgf000114_0001
wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R2, R3, and R4 are defined as above; and wherein PG is independently H, or alkyl(c≤8); or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS, (b) reacting the product obtained in step (a) with a compound of formula I, wherein the coupling of the obtained product and compound of for- mula I is performed via the carboxyl ester of compound I and the X group of the obtained product; (c) reacting the product obtained in step (b) with a compound of formula II in the same way as in step (a); (d) cyclizing the product obtained from step (c) obtaining the product of formula III. 4. Method for the production of a compound of formula III according to claim 1
Figure imgf000115_0002
wherein: X is O, S, or NR; R is H, or alkyl(c≤8); R1 is H, alkyl(c≤8), or cycloalkyl(c≤8); R2 and R3 are each independently H, alkyl(c≤8), (CH2)n (n = 1-5); R4 is independently H, alkyl(c≤8), cycloalkyl(c≤8), alkenyl(c≤8), al- kinyl(c≤8), allyl, propargyl, phenyl, or benzyl; Heterocycle is independently oxazole, thiazol, imidazole, furyl, pyr- rolyl, thiophenyl, pyridyl, or phenyl; * indicate the stereoisomeric centers of the compound; comprising the following steps: (a) reacting a compound of formula I
Figure imgf000115_0001
wherein R and R1 is as defined above; with a compound of formula II
Figure imgf000116_0001
wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R2, R3, and R4 are defined as above; and wherein PG is independently H, or alkyl(c≤8); or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS, (b) reacting the product of step (a) in two different steps, namely step (b1) and step (b2), wherein in step (b1) the compound obtained in step (a) is modified, in a way that PG from X is removed to obtain a compound wherein X is OH, SH, or NH2, and wherein in step (b2) the compound obtained in step (a) is modified, in a way that residue R of the carboxy group is removed and replaced with H; (c) reacting the product obtained in step (b1) with the product obtained in step (b2); (d) cyclizing the product obtained from step (c) obtaining the product of formula III. 5. Method for the production of disorazole-C1 of formula 37
Figure imgf000117_0001
comprising the following steps: (a) reacting a compound of formula 30a
Figure imgf000117_0002
wherein R is methyl or hydrogen with a compound of formula 18
Figure imgf000117_0003
wherein PG1 is MOM obtaining a compound of formula 31
Figure imgf000118_0001
(b) reacting the compound of formula 31 with a compound of formula 30a, obtaining a compound of formula 32
Figure imgf000118_0002
(c) reacting the compound of formula 32 with a compound of formula 18, obtaining a compound of formula 33
Figure imgf000119_0001
(d) reacting compound of formula 33 into disorazole-C1 of formula 37. 6. Method, according to claim 5, wherein step (a) is a coupling reaction combining compounds of formula 18 and of formula 30a, wherein R is methyl. 7. Method, according to claim 5 or 6, wherein step (b) is an esterification. 8. Method, according to at least one of preceding claims 5 to 7, wherein step (c) is a coupling reaction combining compounds of formula 31 and of formula 30a, wherein R is hydrogen. 9. Method, according to at least one of preceding claims 5 to 8, wherein step (d) comprises the following steps: (d1) saponification of methyl ester from compound of formula 33 to a compound of formula 34
Figure imgf000120_0001
(d2) macrolactonisation of open-chained compound 34 into compound of formula 35
Figure imgf000120_0002
(d3) reduction of the triple bonds of compound of formula 35 forming compound of formula 36
Figure imgf000121_0001
(d4) removing the protection groups to obtain compound of formula 37. 10. Method for the production of disorazole-C1 of formula 37
Figure imgf000121_0002
comprising the following steps: (a) reacting a compound of formula 30a
Figure imgf000121_0003
wherein R and Ry are methyl; with a compound of formula 17a
Figure imgf000122_0001
wherein PG1 is methyl and PG2 is MOM; obtaining a compound of formula 40
Figure imgf000122_0002
wherein Rx is PG1 and Ry is methyl as defined above; (b) reacting the compound of formula 40 partially in a step (b1) into a compound of formula 41
Figure imgf000122_0003
and partially in a step (b2) into a compound of formula 42
Figure imgf000123_0001
(c) reacting the compound of formula 41 with the compound of formula 42, obtaining a compound of formula 43
Figure imgf000123_0002
(d) removing Rx and Ry and replacing with hydrogen, obtaining a com- pound of formula 44
Figure imgf000124_0001
(e) reacting compound of formula 44 into disorazole-C1 of formula 37 as described in claim 8, wherein the starting compound is the com- pound of formula 44 instead of formula 34. 11. Intermediate product, for the production according to at least one of the claims 3 to 10, according to formula 30a
Figure imgf000124_0002
wherein R is methyl or hydrogen. 12. Intermediate product, for the production according to at least one of the claims 3 to 9, according to formula 18
Figure imgf000124_0003
wherein PG1 is MOM. 13. Intermediate product, for the production according to at least one of the claims 3 to 10, according to formula 33
Figure imgf000125_0001
wherein PG1 is MOM. 14. Intermediate product, for the production according to at least one of the claims 3 to 10, according to formula I
Figure imgf000125_0002
wherein R and R1 is as defined above. 15. Intermediate product, for the production according to at least one of the claims 3 to 10, according to formula II
Figure imgf000126_0001
wherein X is O, S, or NR as defined above and wherein O, S, or NR comprise further a protective group PG; wherein R2, R3, and R4 are defined as above; and wherein PG is independently H, or alkyl(c≤8); or a protective group se- lected independently from MOM, MEM, THP, TMS, TES, TIPS, TBS, TBDPS. . 16. Pharmaceutical preparation for the treatment of cancer diseases, com- prising at least one compound according to claim 1 and other accepta- ble excipients, adjuvants and /or additives.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018237178A1 (en) 2017-06-22 2018-12-27 William Marsh Rice University Synthesis of disorazoles and analogs thereof as potent anticancer agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018237178A1 (en) 2017-06-22 2018-12-27 William Marsh Rice University Synthesis of disorazoles and analogs thereof as potent anticancer agents

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Title
HARTUNG I V ET AL: "Toward the Total Synthesis of Disorazole A1 and C1: Asymmetric Synthesis of a Masked Southern Segment", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 4, no. 19, 1 January 2002 (2002-01-01), pages 3239 - 3242, XP002265585, ISSN: 1523-7060, DOI: 10.1021/OL026468J *
HILLIER M C ET AL: "The synthesis of the monomeric moiety of disorazole C"1", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM , NL, vol. 41, no. 16, 1 April 2000 (2000-04-01), pages 2821 - 2824, XP004195679, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(00)00271-9 *
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