Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

Abstract

Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C–C and C–N bonds react with amines to allow for the “any-stage” installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release “cyclopentylation” of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral “cyclopentylation” reagents.

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

“…To expand the synthetic viability of incorporating BCP into drug molecules a new method involving the reaction of “spring‐loaded” strained C−C and C−N molecules with amines was developed, enabling the inclusion of BCP at any point in the synthesis. A series of structurally diverse tertiary BCP‐containing amines was synthesized, including derivatized drugs such as maprotiline and amoxapine (Figure ) …”

Residue-Specific Peptide Modification: A Chemist’s Guide

“…45,46 Remarkably, a number of bicyclobutane sulfones and chiral “housanes” were shown to rapidly and selectively functionalize Cys (entry 17) 45,46 in the presence of several unprotected, nucleophilic peptide functional groups.…”

Alkyl and Aryl Thiol Addition to [1.1.1]Propellane: Scope and Limitations of a Fast Conjugation Reaction

“…For example, only thiophenyl itself was used as thiol moiety. The addition of thiols to similar systems, for example, housanes, has already illustrated the importance of such modifications …”