The von Hippel-Lindau (VHL) protein serves as the substrate recognition subunit of the multi-subunit Cullin-2 RING E3 ubiquitin ligase (CRL2^VHL), which regulates intracellular concentrations of hypoxia inducible factors (HIFs) through a ubiquitin proteasome system (UPS) cascade. Strategic recruitment of CRL2^VHL 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.

The preparation and TMSOTf-mediated catalytic carbocupration–silylation of allylic propiolates has been investigated, expanding on previous syntheses of a variety of β-alkyl- and β-aryl-substituted vinylsilanes from an ethyl propiolate precursor. With few exceptions, the series of synthesized O-allyl (E)-vinylsilanes has been isolated in high yields (61–89%) with exceptional diastereoselectivities (E/Z >20:1). Additionally, we demonstrated a novel LDA-initiated, TMSCl-mediated Ireland–Claisen rearrangement of a representative allylic ester.

We aimed to repurpose the non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) rilpivirine (RPV) as a targeted protein degrader (TPD) of HIV-1 RT. Structure-guided modeling identified a TPD bifunctional linker exit trajectory from RPV that threads the NNRTI entrance channel. Ten RPV analogs (RPV’) with varied warhead-linker attachments retained RT inhibition and antiviral activity, guiding selection of an amide-linked connector for degrader construction. We synthesized Proteolysis Targeting Chimeras (PROTACs) designed to recruit CUL4 ^CRBN and CUL2 ^VHL , alongside adamantyl acetic acid-based Hydrophobic Tags (HyTs). TPDs were evaluated for RT inhibition, virus inhibition, biophysical target engagement, and proteasome-dependent degradation. Some PROTACs showed minimal antiviral activity or limited solubility for our assays, whereas the HyT with a tetraethylene glycol (PEG4) linker (PEG4-Ad) exhibited low-nanomolar potency to suppress HIV-1 replication and acceptable solubility. PEG4-Ad reduced RT levels in a proteasome-dependent manner without cytotoxicity but did not exhibit superior potency against RPV resistance mutations. MD simulations suggested that PEG4 linkers maximize episodic exposure of the hydrophobic tag, consistent with PEG4-Ad efficacy. These data highlight the promise—and constraints—of antiviral degraders, indicating that linker-controlled hydrophobic tag exposure and subcellular target accessibility may be critical design parameters for prospective therapeutics.