RESUMEN
The von Hippel-Lindau (VHL) protein serves as the substrate recognition subunit of the multi-subunit Cullin-2 RING E3 ubiquitin ligase (CRL2VHL), which regulates intracellular concentrations of hypoxia inducible factors (HIFs) through a ubiquitin proteasome system (UPS) cascade. Strategic recruitment of CRL2VHL by bi- or trifunctional targeted protein degraders (e.g., PROTACs®) offers the prospect of promoting aberrant polyubiquitination and ensuing proteasomal degradation of disease-related proteins. Non-peptidic, l-hydroxyproline-bearing VHL ligands such as VH032 (1) and its chiral benzylic amine analog Me-VH032 (2), are functional components of targeted protein degraders commonly employed for this purpose. Herein, we compare two approaches for the preparation of 1 and 2 primarily highlighting performance differences between Pd(OAc)2 and Pd-PEPPSI-IPr for the key C-H arylation of 4-methylthiazole. Results from this comparison prompted the development of a unified, five-step route for the preparation of either VH032 (1) or Me-VH032 (2) in multigram quantities, resulting in yields of 56% and 61% for 1 and 2, respectively. Application of N-Boc-l-4-hydroxyproline rather than N-tert-butoxycarbonyl to shield the benzylic amine during the coupling step enhances step economy. Additionally, we identified previously undisclosed minor byproducts generated during arylation steps along with observations from amine deprotection and amidation reaction steps that may prove helpful not only for the preparation of 1 and 2, but for other VHL recruiting ligands, as well.
RESUMEN
The application of a domino radical bicyclization for the synthesis of compounds containing the 1-azaspiro[4.4]nonane skeleton in 11-67% yields as a mixture of diastereomers is described (trans configuration preference). This process involved formation and capture of alkoxyaminyl radicals. For this purpose, O-benzyl oxime ethers with a brominated or iodinated aromatic ring or a terminal alkynyl group and an alkenyl moiety were employed as starting materials. The bicyclization was initiated by 2,2'-azobisisobutyronitrile or triethylborane and promoted by Bu3SnH. The best results were obtained with O-benzyl oxime ethers containing an alkenyl moiety tethered to electron withdrawing groups or aryl substituents, whereas oxime radical precursor attached to methyl-substituted olefin precluded the capture of alkoxyaminyl radical, giving rise mainly to monocyclized product.
