Synthesis of BACE Inhibitor LY2886721. Part I. An Asymmetric Nitrone Cycloaddition Strategy

@article{Kolis2015SynthesisOB,
  title={Synthesis of BACE Inhibitor LY2886721. Part I. An Asymmetric Nitrone Cycloaddition Strategy},
  author={S. Kolis and M. M. Hansen and Enver Arslantas and Lukas Br{\"a}ndli and Jonas Y. Buser and A. C. DeBaillie and A. L. Frederick and D. W. Hoard and Adrienne P. Hollister and Dominique P. Huber and T. Kull and R. J. Linder and T. Martin and Rachel N. Richey and A. Stutz and M. Waibel and J. Ward and A. Zamfir},
  journal={Organic Process Research \& Development},
  year={2015},
  volume={19},
  pages={1203-1213}
}
A scalable, asymmetric synthesis of (3aS,6aS)-6a-(5-bromo-2-fluorophenyl)-1-((R)-1-phenylpropyl)tetrahydro-1H,3H-furo[3,4-c]isoxazole, a key intermediate in the synthesis of LY2886721, is reported. Highlights of the synthesis include the development of an asymmetric [3 + 2] intramolecular cycloaddition facilitated by trifluoroethanol, and the development of a new synthesis of (R)-N-(1-phenylpropyl)hydroxylamine tosylate which proceeds through a p-anisaldehyde imine and avoids the formation of… Expand
6 Citations
Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization
An efficient synthesis of LY2886721 (1) in five steps and 46% overall yield from the chiral nitrone cycloadduct 2 is presented. Minimizing formation of a des-fluoro impurity during hydrogenolysis toExpand
Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints.
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The preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints are described and their design, details of the stereochemically complex organic synthesis, and biological activity are described. Expand
Synthesis, Optimization, and Large-Scale Preparation of the Low-Dose Central Nervous System-Penetrant BACE1 Inhibitor LY3202626 via a [3 + 2] Nitrone Cycloaddition
Herein we report a summary of the synthetic development of LY3202626 from the initial discovery route to a final route that was scaled to make 150 kg. Key developments include the use of a [3 + 2] ...
Optimization of an Aminothiazine Ring Formation: Integrating Modeling with Experiments to Maximize Yield by Minimizing Impurity Formation
The aminothiazine formation step is a key transformation in the process to synthesize a potent and selective inhibitor of Beta-Amyloid Cleaving Enzyme (BACE). There are several impurities formedExpand
Targeting Amyloidogenic Processing of APP in Alzheimer’s Disease
TLDR
Targeting amyloidogenic processing of APP is still a fundamentally sound strategy to develop disease-modifying AD therapies and recent advance in γ-secretase/APP complex structure provides new opportunities in designing selective inhibitors/modulators for AD. Expand

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Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization
An efficient synthesis of LY2886721 (1) in five steps and 46% overall yield from the chiral nitrone cycloadduct 2 is presented. Minimizing formation of a des-fluoro impurity during hydrogenolysis toExpand
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