Preparation of von Hippel-Lindau (VHL) E3 ubiquitin ligase ligands exploiting constitutive hydroxyproline for benzylic amine protection

被引:0
|
作者
Soto-Martinez, Diana M. [1 ]
Clements, Garrett D. [1 ]
Diaz, John E. [1 ]
Becher, Joy [1 ]
Reynolds, Robert C. [2 ]
Ochsenbauer, Christina [2 ]
Snowden, Timothy S. [1 ,3 ]
机构
[1] Univ Alabama, Dept Chem & Biochem, 250 Hackberry Lane, Tuscaloosa, AL 35487 USA
[2] Univ Alabama Birmingham, Dept Med, Div Hematol & Oncol, Birmingham, AL 35294 USA
[3] Univ Alabama, Ctr Convergent Biosci & Med, 720 2nd St, Tuscaloosa, AL 35401 USA
基金
美国国家卫生研究院;
关键词
DEGRADER; IDENTIFICATION; POMALIDOMIDE; BOROHYDRIDE; PRECATALYST; COMPLEXES; NHC;
D O I
10.1039/d4ra01974a
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 (R)) 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. Step economical routes for the multigram preparation of popular VHL E3 ligase recruiting ligands.
引用
收藏
页码:17077 / 17090
页数:14
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