Saturated nitrogen heterocycles are prevalent in pharmaceuticals and agrochemicals, yet boronic acid–derived building blocks remain comparatively underdeveloped relative to heteroaromatic boronic acids. As versatile intermediates for further functionalisation, efficient stereoselective synthetic routes to these compounds are highly desirable. This thesis describes copper-catalysed conjugate borylation strategies for the enantioselective synthesis of boronic ester–functionalised saturated heterocycles, providing modular access to diverse scaffolds.
The first project reports a Cu-catalysed conjugate borylation–cyclisation strategy for the synthesis of boronic ester lactams. A catalyst system derived from CuCl and iPr-FOXAP enabled enantioselective borylation of amino enoates in excellent yields and enantioselectivities. Substrates bearing an α-substituent adjacent to nitrogen underwent borylation with high diastereoselectivity under catalyst control. The resulting β-borylated intermediates were efficiently cyclised to furnish γ-, δ-, and ε-lactam boronic esters without erosion of stereochemical integrity. Exploration of the complementary reactivity of the boronic ester and lactam functionalities further highlights the potential of these compounds as versatile bifunctional building blocks for downstream synthesis.
Building on this platform, the second project extended the methodology to the preparation of 2-substituted pyrrolidine boronic esters. Reactions delivered β-borylated intermediates in consistently high yields and with broad functional-group tolerance. Initial reactions employing the achiral NHC ligand SIMes afforded the desired boronic esters, but with low diastereoselectivity with substrates bearing an α-substituent adjacent to nitrogen. In contrast, implementation of chiral FOXAP ligands enabled highly diastereoselective conjugate borylation.
Subsequent deprotection, cyclisation, and reduction provided access to 2-substituted pyrrolidines. However, purification challenges associated with the free amines necessitated strategic modification. Introduction of an acylation step facilitated isolation, enabling the preparation of a series of N-acylated derivatives in moderate yields and with low diastereoselectivity. Preliminary extension to a six-membered analogue furnished a 2-substituted piperidine boronic ester.
Collectively, this work establishes stereoselective routes to biologically relevant boronic ester-functionalised saturated heterocycles via copper-catalysed conjugate borylation.
