Joseph E. Banning

Formal nucleophilic substitution of bromocyclopropanes with amides en route to conformationally constrained β-amino acid derivatives.

A chemo- and diastereoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides with secondary amides is described. This method allows for convergent and highly selective synthesis of trans-β-aminocyclopropane carboxylic acid derivatives.

Highly Diastereoselective Formal Nucleophilic Substitution of Bromocyclopropanes

A highly diastereoselective formal nucleophilic substitution of bromocyclopropanes with oxygen- and nitrogen-based nucleophiles was demonstrated. The reaction proceeds via a base-assisted dehydrohalogenation producing a cyclopropene intermediate, which subsequently undergoes addition of a pronucleophile across the strained double bond. Very high chemoselectivity toward addition of primary and secondary alkoxides, as well as N-nucleophiles, in the presence of tert-butoxide base was observed, whereas phenoxides did not undergo addition under these reaction conditions. Facial selectivity of the addition can be efficiently controlled either by sterics or through a directing effect of an amide, carboxylate, and an o-aminomethylphenol function. Employment of tethered optically active amino alcohols as pronucleophiles allowed for efficient assembly of homochiral bicyclic compounds.

Diastereoselectivity control in formal nucleophilic substitution of bromocyclopropanes with oxygen- and sulfur-based nucleophiles.

A diastereoconvergent formal nucleophilic substitution of bromocyclopropanes with oxygen- and sulfur-based nucleophiles is described. The reaction proceeds via in situ formation of a highly reactive cyclopropene intermediate and subsequent diastereoselective addition of a nucleophile across the strained C═C bond. Three alternative means of controlling the diastereoselectivity of addition have been demonstrated: (1) thermodynamically driven epimerization of enolizable carboxamides, (2) steric control by bulky substituents, and (3) directing effect of carboxamide or carboxylate functions.

Formal Substitution of Bromocyclopropanes with Nitrogen Nucleophiles

A highly chemo- and diastereoselective protocol toward amino-substituted donor-acceptor cyclopropanes via the formal nucleophilic displacement in bromocyclopropanes is described. A wide range of N-nucleophiles, including carboxamides, sulfonamides, azoles, and anilines, can be efficiently employed in this transformation, providing expeditious access to stereochemically defined and densely functionalized cyclopropylamine derivatives.

Thermodynamic control of diastereoselectivity in the formal nucleophilic substitution of bromocyclopropanes.

A new, general, and chemoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides is described. A wide range of alcohols and phenols can be employed as pronucleophiles in this transformation, providing expeditious access to trans-cyclopropanol ethers. A new mode of the selectivity control through a thermodynamic equilibrium is realized, alternative to the previously described steric and directing modes.