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

Abstract

tert-Butyl 2-substituted 4,6-dioxo-1-piperidinecarboxylates 4 have been prepared in good yield starting from Boc-Asp-O(t)Bu and other beta-amino acids. By analogy with chiral tetramic acids, their reduction by NaBH(4) in CH(2)Cl(2)/AcOH afforded the corresponding cis-4-hydroxy delta-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(t)Bu (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).

Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

“…Just as the pioneering synthetic work of Sir John Cornforth enabled the careful investigation of the mechanisms of enzyme catalysis, the programmed construction of homogeneous peptide and protein targets using the tools afforded by chemical synthesis will no doubt prove an invaluable resource for understanding the intricate relationship between protein structure and function. Madanin-1 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46) Madanin-1 (49-60)…”

“…Madanin-1 (1-27) Chimadanin (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) Chimadanin Chimadanin (1-19)…”

“…This innovative synthetic strategy is particularly attractive for the synthesis of peptides and proteins bearing post-translational modifications on the Lys side-chain, including acetylation, ubiquitylation, and methylation. Access to the key g-thiol Lys building block 20 (Scheme 5) was accomplished in 16 steps from Boc-Asp-OtBu 21 by first employing conditions described by Guichard and co-workers [30] for the preparation of 4-hydroxy Lys precursor 22 bearing a protected g-hydroxy moiety and a free e-hydroxy group. Mesylation and displacement of the primary alcohol of 22 with NaN 3 afforded azide 23, [30] which could be reduced to the corresponding amine using catalytic hydrogenation and re-protected in the presence of Cbz-Cl to afford compound 24.…”

“…Access to the key g-thiol Lys building block 20 (Scheme 5) was accomplished in 16 steps from Boc-Asp-OtBu 21 by first employing conditions described by Guichard and co-workers [30] for the preparation of 4-hydroxy Lys precursor 22 bearing a protected g-hydroxy moiety and a free e-hydroxy group. Mesylation and displacement of the primary alcohol of 22 with NaN 3 afforded azide 23, [30] which could be reduced to the corresponding amine using catalytic hydrogenation and re-protected in the presence of Cbz-Cl to afford compound 24. At this point, the protected g-hydroxy moiety was unmasked and activated using mesyl chloride.…”

Synthesis of a Galactosylated 4‐Hydroxylysine Building Block and Its Incorporation into a Collagen Immunodominant Glycopeptide

“…We have shown previously that enantiopure 5-hydroxy-and 4-hydroxy-6-oxo-1,2-piperidinedicarboxylates are versatile building blocks for the synthesis of 5-and 4-hydroxylysine derivatives, respectively. [5,10] In continuation of this work, we now report the preparation of a N-Fmoc-protected galactosylated (2S,4R)-4-hydroxylysine derivative and its incorporation at position 264 of the CII(256-270) peptide.…”