Synthesis of α-aminoboronic acids

Andrés, Patricia; Ballano, Gema; Calaza, Manuel; Cativiela, Carlos

doi:10.1039/c5cs00886g

Cited by 124 publications

(66 citation statements)

References 132 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, selective decarboxylative borylation at the C terminus of native peptides allowed rapid access to coveted α-amino boronic acids, which are privileged medicinal chemistry motifs (18, 37). Ninlaro ( 1 ), for example, was obtained in three steps from a simple peptide (Fig.…”

Section: Synthetic Applications Of the Decarboxylative Borylation Reamentioning

confidence: 99%

Decarboxylative borylation

Wang

Barton

et al. 2017

Science

352

178

View full text Add to dashboard Cite

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...

show abstract

Section: Synthetic Applications Of the Decarboxylative Borylation Reamentioning

confidence: 99%

Decarboxylative borylation

Wang

Barton

et al. 2017

Science

352

178

View full text Add to dashboard Cite

show abstract

“…1 The nitrogen's reactivity is essentially unchanged compared to standard amines, and coupling of aminoboronates to carboxylic acids is used routinely, for example, in the synthesis of boronic acid-based protease inhibitors such as bortezomib. 2 However, reactions of the nucleophilic C−B bond in, for example, Suzuki coupling, are made more difficult by the adjacent nitrogen atom.…”

mentioning

confidence: 99%

Exploiting the Bis-Nucleophilicity of α-Aminoboronates: Copper-Catalyzed, Intramolecular Aminoalkylations of Bromobenzoyl Chlorides

2016

View full text Add to dashboard Cite

α-Aminoboronate salts are interesting examples of heteroatomic species containing adjacent nucleophilic centers. We have developed an acylation/arylation reaction using 2-bromobenzoyl chlorides as bis-electrophiles that harnesses the nucleophilicity of both positions, leading to isoindolinones. The reactions proceed under mild conditions via an intramolecular, Cu-catalyzed sp(3)-sp(2) coupling, giving products in up to 95% yield. These conditions enable arylation of α,α-disubstituted aminoboronates, which are difficult to accomplish using methods based on less abundant and more expensive transition metals.

show abstract

“…[2] Thei ntroduction of easily transformable functional groups into organoboron compounds would, in principle,g reatly enhance the synthetic values of organoboron compounds for facilitating the modular and rapid synthesis of complex molecules,p rovided that the reactions could be performed in ac hemoselective manner. [5] They have also served as precursors for the synthesis of a-amino boronic acids, [6,7] which are key pharmacophores in proteasome inhibitors. [4] These organoboron compounds have been utilized as synthons in poly-substituted alkene synthesis, for example.…”

mentioning

confidence: 99%

Stereoselective Direct Chlorination of Alkenyl MIDA Boronates: Divergent Synthesis of E and Z α‐Chloroalkenyl Boronates

Zeng

et al. 2017

Angew Chem Int Ed

View full text Add to dashboard Cite

The individual molecules of α-chloroalkenyl boronates include both an electrophilic C-Cl bond and a nucleophilic C-B bond, which makes them intriguing organic synthons. Reported herein is a stereodivergent synthesis of both E and Z α-chloroalkenyl N-methyliminodiacetyl (MIDA) boronates through the direct chlorination of alkenyl MIDA boronates using tBuOCl and PhSeCl reagents, respectively. Both reaction processes are stereospecific and the use of sp -B MIDA boronate is the key contributor to the reactivity. The synthetic value of the boronate products was also demonstrated.

show abstract

Synthesis of α-aminoboronic acids

Cited by 124 publications

References 132 publications

Decarboxylative borylation

Decarboxylative borylation

Exploiting the Bis-Nucleophilicity of α-Aminoboronates: Copper-Catalyzed, Intramolecular Aminoalkylations of Bromobenzoyl Chlorides

Stereoselective Direct Chlorination of Alkenyl MIDA Boronates: Divergent Synthesis of E and Z α‐Chloroalkenyl Boronates

Contact Info

Product

Resources

About