Process for the preparation of epothilones
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Publication Number
US-8030503-B2
Publication Date
2011-10-04
Expiration Date
Abstract
Intermediates in the preparation of epothilones and epothilone analogs are provided along with synthetic methods useful in the synthesis of epothilone compounds.
Core Innovation
The invention relates to a method for preparing an aldehyde compound of a defined formula, including selection of substituents R1, R2, and R3 and the presence of Pg as a hydroxy protecting group. The method proceeds through sequential formation of a reduced product, conversion to a dithioacetal, protection of a hydroxyl group, and final conversion to the aldehyde compound. The structural variation is expressed through the defined groups R6 and R7 in the dithioacetal, including options to form a dithiolane or dithiane ring.
A key aspect of the method is contacting a starting compound with a reducing agent to form a reduced product, followed by contacting the reduced product with a mercaptan reagent and a catalyst to form a dithioacetal compound. The dithioacetal formation is defined by R6 and R7 independently selected from C1-C10 alkyl, phenyl, and benzyl, or optionally combined to form a dithiolane or dithiane ring. This establishes a protected aldehyde precursor framework by leveraging mercaptan-derived dithioacetal chemistry.
Another key aspect is contacting the dithioacetal compound with a hydroxyl protecting group reagent to form a protected compound, followed by converting the protected compound to the aldehyde compound. The document further describes embodiments in which dithioacetal protection and hydroxyl protection are used together in an aldol addition context using a chiral aldol reagent and a chiral auxiliary, including formation of S-configured products and subsequent hydrolysis of the auxiliary to yield a related compound.
Claims Coverage
The document provides independent claims directed to a sequential method with four main inventive phases, chiral aldol preparation, hydroxy protecting group attachment followed by hydrolysis of Aux, and specific compound structural embodiments. Across these claims, the key inventive features include reduction and dithioacetal formation for aldehyde synthesis, chiral aldol stereoselectivity using a chiral auxiliary, hydrolysis of Aux after hydroxy protection, and Markush-defined compound structures with constrained substituent patterns.
Sequential preparation of a defined aldehyde via reduction, dithioacetal formation, hydroxyl protection, and aldehyde conversion
The method prepares an aldehyde compound of the defined formula by contacting a starting compound with a reducing agent to form a reduced product, contacting the reduced product with a mercaptan reagent and a catalyst to form a dithioacetal compound, contacting the dithioacetal compound with a hydroxyl protecting group reagent to form a protected compound, and converting the protected compound to the aldehyde compound.
Chiral aldol formation of a hydroxy-containing compound using a stereoselective chiral auxiliary
A method for preparing a compound of formula (VII) by contacting a compound of formula (VI) with a chiral aldol reagent under conditions sufficient to produce the compound of formula (VII), wherein Aux is a chiral auxiliary that produces a diastereomeric ratio of at least 7 to 1 in favor of an S-configuration at the carbon bearing the hydroxy group.
Hydroxy protecting group attachment followed by hydrolysis of the chiral auxiliary to form a new compound
A method for the preparation of a compound of formula (IX) from a compound of formula (VII) in which each Pg is independently selected, R1, R2, R3 are defined, and Aux is a chiral auxiliary, comprising contacting the compound of formula (VII) with a hydroxy protecting group reagent to attach a protecting group to the hydroxy group and hydrolyzing the Aux group to produce the compound of formula (IX).
Constrained substituent compound formula with R1 and R2 lower-alkyl selection
A compound having a formula wherein R1 is selected from H, unsubstituted lower alkyl, and substituted lower alkyl, and R2 is selected from unsubstituted lower alkyl and substituted lower alkyl.
Constrained substituent compound formula with R1 selection and independent R2/R3 lower-alkyl selection
A compound having a formula wherein R1 is selected from H, unsubstituted lower alkyl, and substituted lower alkyl, and R2 and R3 are each independently selected from unsubstituted lower alkyl and substituted lower alkyl.
Compound formula with hydroxy protecting group and chiral auxiliary/provided substituent proviso
A compound having a formula wherein Ra and Rb are each independently members selected from H and a hydroxy protecting group, Rc is either OH or Aux, R1, R2, and R3 are selected from defined lower-alkyl sets, with a proviso that when R1 is OH, Rb is t-butyldimethylsilyl and Rc is H, then Ra is other than triethylsilyl.
Overall, the independent claims define a method that converts a reduced intermediate into an aldehyde through mercaptan-catalyzed dithioacetal formation and hydroxy protection, a chiral aldol method that uses Aux to achieve an S-configuration with diastereomeric ratio requirements, a method that attaches a hydroxy protecting group and then hydrolyzes Aux, and specific compound structures defined by Markush-style substituent selections and a proviso for particular substituent combinations.
Stated Advantages
Documented Applications
The document links the described intermediates, including compound (IX) after aux hydrolysis, to epothilone synthesis, indicating use in an epothilone intermediate context.
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