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

Abstract

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 toxic hydrogen cyanide gas as a byproduct. The synthesis proceeds over four steps and provides the product in 36% overall yield.

Practical Asymmetric Fluorination Approach to the Scalable Synthesis of New Fluoroaminothiazine BACE Inhibitors

“…Chiral alcohol 4 was synthesized and characterized following standard procedures as described in the literature. 3 All of the reactions were followed by thin-layer chromatography (TLC) analysis (GF254TLC plates , Merck) or liquid chromatography−mass spectrometry (LCMS) using an Agilent 1100 instrument equipped with a solvent degasser, binary pump, autosampler, thermostated column compartment with a two-position/10-port valve, and a diode array detector (Agilent Technologies, Waldbronn, Germany). The UV wavelength was set at 214 nm.…”

“…Thus, we decided to develop a safe, enantioselective, and scalable route for the preparation of compound 3b with the required stereochemistry, taking advantage of the availability of the key chiral amino alcohol intermediate N-[3-[(3S,4R)-3am i n o -4 -( h y d r o x y m e t h y l ) te t r a h y d ro f u r a n -3 -y l ] -4fluorophenyl]acetamide hydrochloride (4) previously reported in the literature. 3 Herein we describe the development of an efficient four-step sequence to deliver 3b on a multigram scale.…”

Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization

“…The establishment of the key cis relative stereochemistry using a nitrone cycloaddition in Step 6 was a key benefit of the route. Issues related to the ketone synthesis and development of an asymmetric nitrone cycloaddition that avoids the late stage resolution were described in Part I, the prior publication in this issue . Described herein is full development of a new route that addresses the issues listed above starting from the asymmetric nitrone cycloaddition product and leading to an efficient synthesis of this complex API.…”

“…Issues related to the ketone synthesis and development of an asymmetric nitrone cycloaddition that avoids the late stage resolution were described in Part I, the prior publication in this issue. 3 Described herein is full development of a new route that addresses the issues listed above starting from the asymmetric nitrone cycloaddition product and leading to an efficient synthesis of this complex API. In addition, the development of a reactive crystallization process that controlled the physical properties of the API is highlighted.…”

“…As described in the prior publication in this issue, an asymmetric nitrone cycloaddition was developed using a chiral auxiliary based approach and afforded the nitrone cycloadduct 2 as a single diastereomer (dr >99.9:0.1, see Scheme 2). 3 As shown in Scheme 3, the first challenge was to convert cycloadduct 2 to an enantiomerically enriched amino alcohol analogous to the racemic amino alcohol used in the firstgeneration route (see Step 7 of Scheme 1). As in the firstgeneration route, the amino alcohol was chosen as a precursor for construction of the aminothiazine ring system.…”