Synthesis of Borylated (Aminomethyl)cyclopropanes Using C1-Bisnucleophiles.

Lithiated 1,1-diborylalkanes have been used as nucleophilic coupling partners with a range of oxygen-based electrophiles, including esters, carbonyls, and epoxides. However, their reactivity with nitrogen-based electrophiles, such as aziridines, has remained relatively understudied. Herein, we show that lithiated 1,1-diborylalkanes react with α-halo and α-tosyl aziridines to yield borylated (aminomethyl)cyclopropanes-a privileged scaffold within medicinal chemistry. The reaction displays high levels of diastereoselectivity, enabling careful control of up to three stereocenters within a single transformation. DFT studies provide insight into the reaction mechanism, which diverges from that observed with analogous epihalohydrin starting materials. Derivatization studies were also performed on the products to demonstrate the utility of the boron and amine handles.

Synthesis of 3-borylated cyclobutanols from epihalohydrins or epoxy alcohol derivatives.

There is an increasing interest in cyclobutanes within the medicinal chemistry community. Therefore, methods to prepare cyclobutanes that contain synthetic handles for further elaboration are of interest. Herein, we report a new approach for the synthesis of 3-borylated cyclobutanols via a formal [3 + 1]-cycloaddition using readily accessible 1,1-diborylalkanes and epihalohydrins or epoxy alcohol derivatives. 1-Substituted epibromohydrin starting materials provide access to borylated cyclobutanols containing substituents at three of the four positions on the cyclobutane core, and enantioenriched epibromohydrins lead to enantioenriched cyclobutanols with high levels of enantiospecificity (>98%). Finally, derivatization studies demonstrate the synthetic utility of both the OH and Bpin handles.

Selective Carbon-Carbon Bond Cleavage of Cyclopropanols.

The carbon-carbon (C-C) bond cleavage of cyclopropanols is a wide area of research with much current activity. This review highlights new developments in this area over the past two decades. A summary is made of the three main reactivity modes, namely, homoenolate chemistry, ß-keto radical chemistry, and acid-catalyzed ring-opening, as well as all other methods for the C-C bond cleavage and functionalization of cyclopropanols, including base-mediated ring-opening, metal-catalyzed C-C insertions and eliminations, oxidative fragmentation using hypervalent iodine reagents, reactions of donor-acceptor cyclopropanols, and pericylic reactions. Emphasis is placed on the synthetic utility of cyclopropanols and related derivatives, which have emerged as unique three-carbon synthons.

Synthesis of Chiral Spin-Labeled Amino Acids.

Spin-labeled amino acids (SLAAs) are often used to determine intermolecular distances and conformations in proteins via double electron-electron resonance. Currently available SLAAs can be difficult to incorporate selectively and have little resemblance to natural side chains in proteins. Enantioselective synthesis of three spin-labeled l-amino acids is described, starting from readily available 2,2,6,6-tetramethyl-4-piperidinone. These SLAAs better replicate canonical residues in proteins and aim for biological incorporation via genetic incorporation or solid-phase peptide synthesis.

Synthesis of trans-2-Substituted Cyclopropylamines from α-Chloroaldehydes.

Cyclopropylamines are prevalent in pharmaceuticals and agrochemicals. Herein, we report the synthesis of trans-2-substituted cyclopropylamines in high diastereoselectivity from readily available α-chloroaldehydes. The reaction proceeds via trapping of an electrophilic zinc homoenolate with an amine followed by ring closure to generate the cyclopropylamine. We have also observed that cyclopropylamine cis/trans-isomerization occurs in the presence of zinc halide salts and that this process can be turned off by the addition of a polar aprotic cosolvent.