Decarboxylative borylation

Abstract

The widespread use of alkyl boronic acids and esters is frequently hampered by the challenges associated with their preparation. We describe a simple and practical method to rapidly access densely functionalized alkyl boronate esters from abundant carboxylic substituents. This broad-scope nickel-catalyzed reaction uses the same activating principle as amide bond formation to replace a carboxylic acid moiety with a boronate ester. Application to peptides allowed expedient preparations of α-amino boronic acids, often with high stereoselectivity, thereby facilitating synthesis of the alkyl boronic acid drugs Velcade and Ninlaro as well as a boronic acid version of the iconic antibiotic vancomycin. The reaction also enabled the discovery and extensive biological characterization of potent human neutrophil elastase inhibitors, which offer reversible covalent binding properties.

Fig. 1. Development of the decarboxylative borylation reaction

(A) Strategic value of the decarboxylative borylation illustrated through the retrosynthetic analysis of Ninlaro (1). (B) Development and optimization of the decarboxylative borylation reaction. Footnotes: *Reaction conducted on 0.10 mmol scale. ^†Yield by gas chromatography. ‡Isolated yield.

Fig. 2. Scope of the Ni-catalyzed decarboxylative borylation reaction of redox-active esters

Standard reaction conditions: Redox-active NHPI ester (1.0 equiv), NiCl₂•6H₂O (10 mol %), L1 (13 mol %), MgBr₂•OEt₂ (1.5 equiv), [B₂pin₂ (3.3 equiv), MeLi (3.0 equiv)] precomplexed,THF/DMF (2.5:1), 0°C to room temperature, 2 hours. Footnotes: *Using THF as the solvent. ^†Using L2 as the ligand. ‡Using tetrachloro-NHPI (TCNHPI) ester. §Using 1.0 equiv of MgBr₂•OEt₂. ¶Using 2.5 mol % of NiCl₂•6H₂O and 3.3 mol % of ligand (L1 or L2). (See supplementary materials for experimental details.)

Fig. 3. Applications of the decarboxylative borylation reaction

(A) Late-stage diversification of Lipitor. (B) Synthesis and biological evaluation of 44, a boronic acid analog of vancomycin. (C) Probing the stereoselectivity of peptide substrates and the ensuing stereoselective synthesis of Velcade (49). Footnotes: *VRE(VanA). ^†VRE(VanB). ‡Yield and diastereoselectivity refer to the decarboxylative borylation of the corresponding RAE. See supplementary materials for experimental details.

Fig. 4. Discovery of novel human neutrophil elastase (HNE) inhibitors

(A) Structures of selected elastase inhibitors. (B) IC₅₀ values (nM) of selected elastase inhibitors (average ± SD, n = 3 plotted, representative of three independent, triplicate experiments). A nonlinear three-parameter log inhibitor curve was used to calculate the IC₅₀ values. Curve fit statistics: Purified HNE, R² ≥ 0.95; CF patient sputum, R² ≥ 0.93; COPD patient sputum, R² ≥ 0.93. (C) ADME profile of 51, 51a, and 52.

Fig. 5. A graphical guide to the decarboxylative borylation reaction

(A) General transformation and materials for the reaction. (B) Addition of reagents. (C) Observations during the reaction. (D) Work-up and purification of the reaction mixture.