Α-boryl Aldehydes Research Articles

An Exploration of Regioselectivity During Formation of Aminoboronates from Epoxides

Abstractα-Aminoboronic acids and their derivatives are important synthetic targets. Our research interest has been focused on the synthesis and applications of MIDA (N-methyliminodiacetic acid) protected aminoboronates. Herein we report syntheses of regioisomeric β-borylated azidoalcohols. The geminal azidoboronate represents a rare example of an α-azidoalcohol and is produced through trapping of oxonium ions that develop during the rearrangement of α-boryl aldehydes. The vicinal azidoboronate can be obtained from α-bromoacetyl MIDA boronate and enables the preparation of aziridine MIDA boronate through the Staudinger reaction.

Modular Access to Diverse Amphoteric α-Boryl Aldehydes or Borylated Heterocycles via Photoredox Catalysis

Modular Access to Diverse Amphoteric α-Boryl Aldehydes or Borylated Heterocycles via Photoredox Catalysis

Synthesis of Fluorinated Aminoalkylboronic Acids from Amphoteric α-Boryl Aldehydes.

Our ongoing search for underdeveloped functional group combinations has brought to light α-fluorinated aminoalkylboronic acids, a new class of molecules featuring the B-CF linkage. These compounds can now be generated from secondary amines and α-boryl aldehydes through electrophilic fluorination of boryl enamines or enamides. Fluorinated β-aminoalkylboronic acids show no signs of degradation under ambient conditions. We present evidence for the involvement of chair-like motifs, favored over the acyclic forms by up to 1.7±0.1 kcal mol-1 in water and held together by an amine-boronate hydrogen bond. Fluorinated β-aminoalkylboronic acids are stable over a wide pH range and are characterized by a pKa of 3.4, which is the lowest of any alkylboronic acid.

Borylated oximes: versatile building blocks for organic synthesis.

Herein, we demonstrate the synthesis and functionalization of α-boryl aldoximes from α-boryl aldehydes, with no sign of C-to-N boryl migration. Selective modification of the oxime functionality enables access to a wide range of borylated compounds, such as borylated heterocycles and N-acetoxyamides. By reducing the α-boryl aldoximes, MIDA deprotection yields the corresponding β-boryl hydroxylamines. As part of this study, we also demonstrate the utility of the boryl aldoxime motif in peptide conjugation.

Synthesis of Aminoboronic Acid Derivatives from Amines and Amphoteric Boryl Carbonyl Compounds.

Herein, we demonstrate the use of α-boryl aldehydes and acyl boronates in the synthesis of aminoboronic acid derivatives. This work highlights the untapped potential of boron-substituted iminium ions and offers insights into the behavior of N-methyliminodiacetyl (MIDA) boronates during condensation and tautomerization processes. The preparative value of this contribution lies in the demonstration that various amines, including linear and cyclic peptides, can be readily conjugated with boron-containing fragments. A mild deprotection of amino MIDA-boronates enables access to α- and β-aminoboronic acids in high chemical yields. This simple process should be applicable to the synthesis of a wide range of bioactive molecules as well as precursors for cross-coupling reactions.

Access to Cyclic Amino Boronates via Rhodium-Catalyzed Functionalization of Alkyl MIDA Boronates.

Herein, we describe the rhodium-catalyzed C-H amination reaction of 1,2-boryl sulfamate esters derived from amphoteric α-boryl aldehydes. Depending on the substitution pattern of the boryl sulfamate ester, a diverse range of five- or six-membered ring heterocycles are accessible using this transformation. The highly chemoselective nature of the C-H functionalization reaction preserves the alkyl boronate functional group, which enables the synthesis of B-C-N and B-C-C-N motifs that are present in a number of hydrolase inhibitors.

Amphoteric α-Boryl Aldehyde Linchpins in the Synthesis of Heterocycles

Pairing of mutually reactive functional groups in the same molecule affords enabling opportunities in chemical synthesis. Kinetically amphoteric molecules exemplify this scenario and help avoid the pitfalls of protecting-group chemistry by exploiting the innate reactivity of the functional groups. In this perspective, we highlight the recent development of MIDA (N-methyliminodiacetyl) α-boryl aldehydes as amphoteric building blocks that act as linchpins in the synthesis of heterocycles. This short review includes topics ranging from metal-catalyzed cyclization involving B–C–Pd intermediates to the intramolecular Suzuki–Miyaura cross-coupling that affords six- and seven-membered rings. The use of boryl aldehydes in other transformations, including halogenation and oxidation protocols, is also discussed.

From synthesis to function via iterative assembly of N-methyliminodiacetic acid boronate building blocks.

The study and optimization of small molecule function is often impeded by the time-intensive and specialist-dependent process that is typically used to make such compounds. In contrast, general and automated platforms have been developed for making peptides, oligonucleotides, and increasingly oligosaccharides, where synthesis is simplified to iterative applications of the same reactions. Inspired by the way natural products are biosynthesized via the iterative assembly of a defined set of building blocks, we developed a platform for small molecule synthesis involving the iterative coupling of haloboronic acids protected as the corresponding N-methyliminodiacetic acid (MIDA) boronates. Here we summarize our efforts thus far to develop this platform into a generalized and automated approach for small molecule synthesis. We and others have employed this approach to access many polyene-based compounds, including the polyene motifs found in >75% of all polyene natural products. This platform further allowed us to derivatize amphotericin B, the powerful and resistance-evasive but also highly toxic last line of defense in treating systemic fungal infections, and thereby understand its mechanism of action. This synthesis-enabled mechanistic understanding has led us to develop less toxic derivatives currently under evaluation as improved antifungal agents. To access more Csp(3)-containing small molecules, we gained a stereocontrolled entry into chiral, non-racemic α-boryl aldehydes through the discovery of a chiral derivative of MIDA. These α-boryl aldehydes are versatile intermediates for the synthesis of many Csp(3) boronate building blocks that are otherwise difficult to access. In addition, we demonstrated the utility of these types of building blocks in accessing pharmaceutically relevant targets via an iterative Csp(3) cross-coupling cycle. We have further expanded the scope of the platform to include stereochemically complex macrocyclic and polycyclic molecules using a linear-to-cyclized strategy, in which Csp(3) boronate building blocks are iteratively assembled into linear precursors that are then cyclized into the cyclic frameworks found in many natural products and natural product-like structures. Enabled by the serendipitous discovery of a catch-and-release protocol for generally purifying MIDA boronate intermediates, the platform has been automated. The synthesis of 14 distinct classes of small molecules, including pharmaceuticals, materials components, and polycyclic natural products, has been achieved using this new synthesis machine. It is anticipated that the scope of small molecules accessible by this platform will continue to expand via further developments in building block synthesis, Csp(3) cross-coupling methodologies, and cyclization strategies. Achieving these goals will enable the more generalized synthesis of small molecules and thereby help shift the rate-limiting step in small molecule science from synthesis to function.

ChemInform Abstract: Boron‐Containing Enamine and Enamide Linchpins in the Synthesis of Nitrogen Heterocycles.

The use of α-boryl enamine and enamide linchpins in the synthesis of nitrogen heterocycles has been demonstrated. Boryl enamines provide ready access to the corresponding α-halo aldehydes, which undergo regioselective annulation to form borylated thiazoles. A condensation/amidation sequence converts α-boryl aldehydes into stable α-boryl enamides without concomitant C → N migration. We also show that palladium-catalyzed cyclization of α-boryl enamides leads to synthetically versatile isoindolones. These molecules can be subsequently used to access polycyclic scaffolds.

Boron-containing enamine and enamide linchpins in the synthesis of nitrogen heterocycles.

The use of α-boryl enamine and enamide linchpins in the synthesis of nitrogen heterocycles has been demonstrated. Boryl enamines provide ready access to the corresponding α-halo aldehydes, which undergo regioselective annulation to form borylated thiazoles. A condensation/amidation sequence converts α-boryl aldehydes into stable α-boryl enamides without concomitant C → N migration. We also show that palladium-catalyzed cyclization of α-boryl enamides leads to synthetically versatile isoindolones. These molecules can be subsequently used to access polycyclic scaffolds.

ChemInform Abstract: α‐Borylcarbonyl Compounds: From Transient Intermediates to Robust Building Blocks

AbstractReview: 71 refs.

ChemInform Abstract: Air‐ and Moisture‐stable Amphoteric Molecules: Enabling Reagents in Synthesis

AbstractReview: 51 refs.

Air- and Moisture-Stable Amphoteric Molecules: Enabling Reagents in Synthesis

Researchers continue to develop chemoselective synthesis strategies with the goal of rapidly assembling complex molecules. As one appealing approach, chemists are searching for new building blocks that include multiple functional groups with orthogonal chemical reactivity. Amphoteric molecules that possess nucleophilic and electrophilic sites offer a versatile platform for the development of chemoselective transformations. As part of a program focused on new methods of synthesis, we have been developing this type of reagents. This Account highlights examples of amphoteric molecules developed by our lab since 2006. We have prepared and evaluated aziridine aldehydes, a class of stable unprotected α-amino aldehydes. Structurally, aziridine aldehydes include both a nucleophilic amine nitrogen and an electrophilic aldehyde carbon over the span of three atoms. Under ambient conditions, these compounds exist as homochiral dimers with an aziridine-fused five-membered cyclic hemiaminal structure. We have investigated chemoselective reactions of aziridine aldehydes that involve both the aziridine and aldehyde functionalities. These transformations have produced a variety of densely functionalized nitrogen-containing compounds, including amino aldehydes, 1,2-diamines, reduced hydantoins, C-vinyl or alkynyl aziridines, and macrocyclic peptides. We have also developed air- and moisture-stable α-boryl aldehydes, another class of molecules that are kinetically amphoteric. The α-boryl aldehydes contain a tetracoordinated N-methyliminodiacetyl (MIDA) boryl substituent, which stabilizes the α-metalloid carbonyl system and prevents isomerization to its O-bond enolate form. Primarily taking advantage of chemoselective transformations at the aldehyde functionality, these α-boryl aldehydes have allowed us to synthesize a series of new functionalized boron-containing compounds that are difficult or impossible to prepare using established protocols, such as α-borylcarboxylic acids, boryl alcohols, enol ethers, and enamides. Using α-borylcarboxylic acids as starting materials, we have also prepared several new amphoteric borylated reagents, such as α-boryl isocyanates, isocyanides, and acylboronates. These compounds are versatile building blocks in their own right, enabling the rapid synthesis of other boron-containing molecules.

ChemInform Abstract: Amphoteric α‐Boryl Aldehydes.

AbstractNovel α‐boryl aldehydes (II) are prepared via rearrangement of oxiranyl N‐methyliminodiacetyl boronates (I).

Chemoselective palladium-catalyzed α-allylation of α-boryl aldehydes

Herein we report the development of an α-allylation reaction of α-boryl aldehydes that preserves the carbon-boron bond under Pd(0)/Pd(II) catalysis. A variety of α-boryl aldehydes and allylic alcohols participate in this chemoselective transformation. The α-allylated products were obtained as single regioisomers.

Amphoteric α-Boryl Aldehydes

A new class of stable molecules, α-boryl aldehydes, has been prepared from oxiranyl N-methyliminodiacetyl boronates by a 1,2-boryl migration with concomitant epoxide scission. A range of boryl imines, alkenes, alcohols, acids, enol ethers, enamides, and other functionalized boronic acid derivatives that are difficult or impossible to prepare using established protocols can be accessed from α-boryl aldehydes. The chemoselective transformations of these building blocks, including the facile synthesis of functionalized unnatural amino acids from silyloxy and amido vinyl boronates, attest to the potential of α-boryl aldehydes in chemical synthesis.

Pinene-Derived Iminodiacetic Acid (PIDA): A Powerful Ligand for Stereoselective Synthesis and Iterative Cross-Coupling of C(sp3) Boronate Building Blocks

Efficient access to chiral C(sp3) boronates in stereochemically pure form is critical for realizing the substantial potential of such building blocks in complex-molecule synthesis. We herein report that a pinene-derived iminodiacetic acid (PIDA) ligand enables the highly diastereoselective synthesis of a wide range of oxiranyl C(sp3) boronates from the corresponding olefins. These oxiranyl PIDA boronates, in turn, can be readily transformed into unprecedented stable α-boryl aldehydes via a novel 1,2-migration of the boronate group that proceeds with complete maintenance of stereochemical purity. B-Protected haloboronic acids containing dual sp3-hybridized C centers are readily accessible via this platform, and the herein demonstrated capacity for stereocontrolled iterative C(sp3) cross-coupling with this novel type of bifunctional reagent to access a medicinally important chiral small-molecule target in highly enantioenriched form represents a substantial advance for the building-block-based approach to synthesis.