1P27: y) Synthesis of highly potent benzodiazepine γ-secretase inhibitors

I. Churcher et al.⁶⁵ designed novel benzodiazepine containing γ-secretase inhibitors for potent use in Alzheimer’s diseases. A syn combination of α-alkyl or aryl β-hydroxy or hydroxyl methyl substituents was shown to give highly potent compounds. Initially the introduction of a hydroxyl group into the β-position of the hydrocinnamide side chain was investigated. In the case where the α-substituent was methyl, this was carried out using the Evans oxazolidinone chiral auxiliary methodology⁶⁶ to yield the syn- or anti-aldol adduct with eitherabsolute stereochemistry. Coupling to the known, homochiral benzodiazepine⁶⁷ (155) yielded the desired amides (151-154) as shown in Scheme 27a.

Functionalization of syn-aldol (151) was possible to yield adducts (156-159); alternatively, oxidation of 151 gave the β-keto amide (160) (exclusively in the keto form in CDCl₃ solution) as a mixture of diastereomers. Treatment with the appropriate hydroxylamine yielded the oximes (161) and (162), again as mixtures of isomers. When the above route was applied to the preparation of α-4-fluorophenyl-substituted aldol analogues, significant retro-aldol reaction was observed at the LiOH/ H₂O₂-mediated auxiliary cleavage step, necessitating the use of a silyl protecting group. This modification allowed the preparation of the desired syn isomers 163-166 as outlined in Scheme 27b.

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65. I. Churcher, S. Williams, S. Kerrad, T. Harrison, J. L. Castro, M. S. Shearman, H. D. Lewis, E. E. Clarke, J. D. J. Wrigley, D. Beher, Y. S. Tang, and W. Liu, J. Med. Chem., 2003, 46,  2275.

66. D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc., 1982, 104, 1737.
67. P. J. Reider, P. Davis, D. L. Hughes, E. J. J. Grabowski, J. Org. Chem., 1987, 52, 955.
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