Decarboxylative borylation

Abstract

INTRODUCTION The boronic acid is a functional group of enormous utility in materials science, chemosensor development, and drug discovery. In medicinal chemistry, boronic acids have been harnessed as a replacement for various structural motifs (a bioisostere) to improve the potency or pharmacokinetic profiles of lead compounds. However, the widespread incorporation of alkyl boronic acids has been largely hampered by the challenges associated with their preparation. Consequently, only two alkyl boronic acids are currently in clinical use, namely Velcade and Ninlaro. Few methods are capable of delivering alkyl boronates from readily available starting materials; most exhibit modest functional group compatibility. Indeed, boronate motifs are often installed at the early stage of a synthesis and thus consume disproportionate effort from the standpoint of planning and manipulation in multistep processes. RATIONALE Alkyl carboxylic acids, as the most variegated chemical building blocks on Earth, are present in a myriad of natural products and medicines. They represent an ideal precursor to boronic acids. Previous efforts from our laboratory revealed that, through the intermediacy of simple redox-active esters (RAEs, e.g., N-hydroxyphthalimide esters), alkyl carboxylic acids could be harnessed as convenient alkyl halide surrogates in metal-catalyzed decarboxylative cross-coupling reactions with carbon nucleophiles, using the same activating principles as amide bond formation. It was therefore surmised that such reactivity could be exploited in a decarboxylative borylation process wherein structurally diverse and ever-present carboxylic acids could be converted directly into high-value boronic acids. RESULTS Through the exclusive use of N-hydroxyphthalimide RAEs, a simple means to convert carboxylic acids into boronate esters was enabled with an inexpensive nickel catalyst. This reaction was broad in scope (>40 examples) and demonstrated excellent functional group compatibility (tolerating alkyl/aryl halides, amides/carbamates, alcohols, ketones, and olefins), and high levels of diastereoselectivity, allowing transformations of densely functionalized drug molecules (e.g., vancomycin and Lipitor) and natural products (e.g., enoxolone) into the analogous boronic acids. This method’s unique capacity to access α-amino boronic acids from native peptides not only allowed the concise syntheses of both Velcade and Ninlaro, it also enabled the expedient discovery of three highly potent human neutrophil elastase (HNE) inhibitors, the most potent of which has shown improved in vitro inhibitory activities (IC50 = 15 pM, Ki = 3.7 pM) relative to leading candidates previously tested in clinical trials. Enzymatic and pharmacokinetic studies indicated high functional stability in physiologically relevant media. CONCLUSION The nickel-catalyzed decarboxylative cross-coupling of RAEs enables substitution of ubiquitous alkyl carboxylic acids with boronate esters using an inexpensive boron source: B2pin2 (Bpin = pinacol boronate). Th...

Residue-Specific Peptide Modification: A Chemist’s Guide

“…Nevertheless, orthogonal protecting group strategies and judicious sequence choice have been employed to enable several decarboxylative functionalizations of α -acids, including 1,4-additions (entry 44), 79 heteroarylations (entry 45), 80,81 and borylations (entry 46). 82 …”

New radical methods for the potential synthesis of carbon‐13 and carbon‐14 labeled complex products

“…Redox‐active esters were either isolated or formed in situ and then reacted with a nickel or iron catalyst and one of the eight ligands, L1–L8, shown in Figure . The majority of the reactions described in this review used ligands L1, L2, L3, or L5 . During the reaction, redox‐active esters react with the nickel or iron catalyst to eliminate carbon dioxide through electron transfer redox chemistry to generate a radical intermediate which reacts with various compounds to generate a wide range of products as shown in Scheme .…”

“…It also has been applied to the formation of complex products 92 (80% yield) from naproxen, 93 (65% yield) from dehydrocholic acid, product 94 (50% yield), and product 95 (57% yield) from atorvastatin. Although this method does not directly provide a means for incorporating carbon‐13 or carbon‐14 isotopic labels, the resulting Bpin ester products do provide a handle for Suzuki couplings with other appropriately substituted isotopic labeled molecules or as a means to couple with redox‐active esters as described in Section 4.2 …”

“…Nickel catalyzed coupling reactions between redox‐active esters and B 2 pin 2 to generate substituted Bpin products…”

Decarboxylative C(sp3)–N cross-coupling via synergetic photoredox and copper catalysis

“…Extension to a decarboxylative carbon-heteroatom, particularly C-B bond formation has also been reported 19,[25][26][27][28][29] . The key attributes of alkyl carboxylic acids 30,31 are their unparalleled availability, stability and non-toxic nature, which are in stark contrast with alkyl halides, ketones and aldehydes.…”