Part I. Stereoselective Synthesis of Geminal Bromofluoroalkenes by Kinetic Differentiation of Oxaphosphetane Intermediates Part II. Investigation of Stereoselective Alkene Synthesis via 4π-Electrocyclization of Aldazine Derivatives

Abstract

Part I: Geminal bromofluoroalkenes are an important subclass of versatile organic interhalides, but the widely applicable stereoselective synthesis remained elusive before our work. In particular, the Wittig-type haloolefination had been unsuccessful because of the difficulty in the diastereoselective oxaphosphetane formation. Thus, a thermodynamically controlled stereoselective approach in the Wittig-type interhaloolefination was investigated via the addition of lithium cation to establish an equilibrium between the betaine intermediates. Unfortunately, despite the exhaustive survey of various lithium salts and phosphorus(III) reagents with modulated steric and electronic properties, the reaction suffered from intermediate decomposition and poor reproducibility. Alternatively, high stereoselectivity could be attained via selectively converting one of the oxaphosphetane intermediates. The suitably identified phosphonite and non-polar reaction medium enabled efficient kinetic differentiation. Through our method, the highly diastereoselective synthesis of geminal E-bromofluoroalkenes was accomplished conveniently in one step from a wide range of readily available carbonyl compounds, including ketones and pharmaceutically relevant substrates. Furthermore, upon extensive efforts to expand this newly discovered strategy to other haloolefinations, α-bromoacrylate was successfully afforded with excellent selectivity. Part II: The stereoselective synthesis of alkenes was explored via 4π-electrocyclization of aldazines and aldazine N-oxides. To promote a conformational change to requisite but less favorable s-cis, N-functionalization and bimetallic complexation were examined. Unfortunately, aldazine derivatives remained unreacted, or a complex mixture was produced. In order to enhance the reactivity of aldazine by polarization of 4π-system, an unsymmetrically functionalized push-pull structure was prepared. However, the desired 4π-electrocyclization did not proceed. Furthermore, investigation of charged N-carbo-functionalized aldazinium formation via oxidation of hydrazone precursors resulted in decomposition of the substrates. Then, sequential 4π-electrocyclic ring opening and cyclization of N-aziridinyl imines as well as the use of macrocyclic ketazines were attempted, but the substrate preparation was unsuccessful.