Synthesis of Enantiopure 4-Hydroxypipecolate and 4-Hydroxylysine Derivatives from a Common 4,6-Dioxopiperidinecarboxylate Precursor

tert-Butyl 2-substituted 4,6-dioxo-1-piperidinecarboxylates 4 have been prepared in good yield starting from Boc-Asp-O^tBu and other β-amino acids. By analogy with chiral tetramic acids, their reduction by NaBH₄ in CH₂Cl₂/AcOH afforded the corresponding cis-4-hydroxy δ-lactams in good yield and stereoselectivity (68−98% de). In the absence of the A(1,3) strain (reduction of 6-substituted 2,4-dioxo-1-piperidines 7), the cis-4-hydroxy isomer was still obtained as the major product but the de values were consistently lower. 4-Hydroxy-6-oxo-1,2-piperidinedicarboxylate 2a, readily accessible from Boc-Asp-O^tBu (three steps, 63% overall yield), has proven to be an excellent building block for the synthesis of cis- and trans-4-hydroxypipecolates 17 and 24 (52 and 36% overall yield, respectively) and for the synthesis of a protected 4-hydroxylysine derivative 29 (41% overall yield).