The development of two efficient strategies for the synthesis of
AZD4407 is reported, both of which are considered suitable
for large-scale manufacture. In the first approach, 3-bromothiophene is coupled with (2S)-2-methyltetrahydropyran-4-one using Grignard chemistry. Following hydroxyl protection
and lithiation at thiophene C-2, reaction with a protected
5-mercapto-1-methyl-1,3-dihydro-indol-2-one derivative bearing
a leaving group on sulphur provides AZD4407 after acid-catalysed deprotection and epimerisation. The second approach
starts from 2,4-dibromothiophene, which undergoes a selective
Grignard exchange reaction at C-2 followed by reaction with
similar protected mercapto-oxindole derivatives. Reprotection
of the oxindole ring, followed by a second Grignard exchange,
and reaction with (2S)-2-methyltetrahydropyran-4-one provides
AZD4407 after acid-catalysed deprotection and epimerisation.
Thermolysis of the (2€,8Z)-9-(2-fury1)nonadienoate 25 at 290 "C leads to an essentially quantitative yield of a single furanodecalin 26, whereas the corresponding (2€,8€)-isomer 34 undergoes a non-stereoselective cyclisation leading to the furanodecalins 26 and 35. (Z) -Alkenoate functions undergo partial isomerisation prior to cyclisation and so lead to mixtures of isomers. Alkyl groups can be incorporated around the reaction sites, but this can result in overwhelming competition from side reactions. The corresponding 3-fury1 analogues 56 and 59 display very similar reactivities.
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