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.

α-Borylcarbonyl species (C-bound boron enolates) are typically unstable due to their kinetic and thermodynamically favourable rearrangement to their O-bound isomers. Direct evidence of α-borylcarbonyl compounds is sparse despite the multitude of transformations in which they have been implicated as reactive intermediates. In recent years, a few examples have emerged of reactive α-borylcarbonyl intermediates that can be observed using spectroscopic methods. Other reports have shown that certain compounds containing the α-borylcarbonyl motif can be isolated under ambient conditions. Installation of electron-rich, tetracoordinate sp(3)-boron centers is a particularly viable strategy to improve the stability of α-borylcarbonyl systems as it imposes a barrier to the otherwise rapid 1,3-boron shift from carbon to oxygen. Among stable α-borylcarbonyl compounds, α-boryl aldehydes, equipped with a tetracoordinated N-methyliminodiacetyl (MIDA) boryl group, have been demonstrated to be versatile building blocks in the synthesis of a wide range of functionalized organoboron compounds.

a] The reactions were carried out by stirring a-boryl isocyanate (1.0 equiv), trichlorosilane (1.6 equiv), and triethylamine (3.6 equiv) in anhydrous CH 2 Cl 2 at 0 8C for 30 min and subsequent stirring for 6 h at 23 8C.[b] Yields of isolated products after silica gel chromatography.

An efficient and versatile synthesis of chiral tetralins has been developed using both inter- and intramolecular Friedel-Crafts alkylation as a key step. The readily available hydronaphthalene substrates were prepared via a highly enantioselective metal-catalyzed ring opening of meso-oxabicyclic alkenes followed by hydrogenation. A wide variety of complex tetracyclic compounds have been isolated with high levels of regio-, diastereo-, and enantioselectivity.

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.