High yield preparation of cytotoxic or fungicidal compound epothilon B, from phenylsulfonyl-butanol derivative by multistage process via new thiazole derivative intermediates

摘要

Epothilon B (or its derivative) (I) is prepared by a multi-stage route from protected (3S)-4-hydroxy-3-methyl-1-phenylsulfonyl-butane (III) via new 4-(substituted alkadienyl)-2-methyl-thiazole derivatives (IV) and (V). The preparation of epothilon B compounds of formula (I) involves: (1) reacting a protected (3S)-4-hydroxy-3-methyl-1-phenylsulfonyl-butane of formula (III) with a thiazole derivative of formula (IV) to give a thiazolyl-substituted protected diol of formula (V); (2) reacting with an oxo-substituted protected diol of formula (II) to give a thiazole derivative of formula (VI); (3) converting (VI) via compounds of formula (VII; Q = CH2OTBS; Q' = TBS), (VII; Q = CH2OH; Q' = TBS), (VII; Q = COOH; Q' = TBS), (VII; Q = COOH; Q' = H) and (VIII; Q'' = TBS) into an epothilon D compound of formula (VIII; Q'' = H); and (4) epoxidizing to give (I). R6 = 1-6C alkyl. 4-10C cycloalkylalkyl, Ph, 1- or 2-naphthyl, benzyl or methylheteroaryl; F' = phenylsulfonyl; P' = hydroxy-protecting group; F'' = I or other leaving group; TBS = tert. butyl-dimethylsilyl. Independent claims are included for: (1) the preparation of (II), by: (a) reacting an aldehyde of formula P'CH2CH2CHO (IIa) under chiral catalysis with a silylketene acetal of formula (Me)2C=C(OR2)OSi(Me)3 (IIIa) in presence of N-tosyl-valine/diborane to give an ester of formula (IVa) (b) converting into a 3-hydroxy-protected compound of formula (IVb) (c) adding a methyl group at the carbonyl group to give a ketone of formula (Va) and (d) reacting with a halide of formula R6-Hal to give (II); or alternatively reducing (IVb) to an alcohol, oxidizing selectively to an alcohol, adding a -CH2R6 group using an organometallic reagent and oxidizing the obtained alcohol to the ketone (II); (2) the preparation of (III) by converting the free hydroxy group of an alcohol of formula (IIIb) into a better leaving group then introducing the CH2F' group by displacement of the leaving group; and (3) (V) and (VI) as new compounds. R2 = Me, Et, etc (sic); Hal = F, Cl or Br.