Enantiodivergent Cyclization by Inversion of the Reactivity in Ambiphilic Molecules

Abstract

Inverting the reactivity of the functional groups in ambiphilic molecules provides a new synthetic strategy to perform late‐stage enantiodivergence. Both enantiomers of the final compound can be obtained from a common chiral precursor. As a proof of concept, the synthesis of substituted five‐ and six‐membered oxacycles is described. The key step is the cyclization of an ambiphilic linear precursor bearing a propargylic alcohol and an epoxide linked through an alkyl chain. Through a slight modification of these linear precursors and employing different reaction conditions, these functional groups can inverse their chemical reactivity, producing one enantiomer or another of the final product. This enantiodivergent cyclization involves three stereogenic centers that can undergo fully controlled retention or inversion of their configuration depending on the cyclization pathway that is activated. The cyclization provides late‐stage enantiodivergence, enabling the synthesis of either enantiomers of the oxacycles from a common chiral substrate with total transfer of the enantiomeric purity.

Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes

“…An extensive list of nucleophiles has been employed in this transformation, from carbon-based entities such as ketones and enol silanes, to nitrogen nucleophiles such as amines and sulfonamides, or oxygen centered species such as alcohols [ 12 , 13 ] or epoxides [ 14 , 15 ]. In the case where the nucleophile is connected to the alkyne via a suitable chain, the Nicholas reaction will result in intramolecular attack and formation of a ring [ 12 , 13 ].…”