Organic chemistry. Strain-release amination

Abstract

To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C-C and C-N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.

Fig. 1. Synthetic methods for incorporating small, strained ring systems

(A) Revisiting the retrosynthetic disconnection of an important scaffold in medicinal chemistry, bicyclo[1.1.1]pentan-1-amine. (B) Strain release amination: any-stage functionalization of lead compounds in drug discovery.

Fig. 2. “Propellerization” of amine-containing substrates. Isolated yields are reported

(A) An improved synthesis of the known bicyclo[1.1.1]pentan-1-amine. (B) A general “propellerization” of amines enabled by strain release reagents. (C) Substrate scope of amine-containing substrates.

Fig. 3. “Azetidinylation” of amine-containing substrates

(A) A general “azetidinylation” of amines enabled by strain release reagents. (B) Scope of amine-containing substrates.

Fig. 4. Cyclobutylation of amine-containing substrates

(A) A general cyclobutylation of amines with C7 enabled by strain release reagents. (B) Substrate scope of amine-containing substrates. (C) Diversification of intermediate cyclobutylsulfone 76. (D) Installation of cyclopentane onto primary and secondary amines by strain release amination.

Fig. 5. Use of reagent C as a chemoselective cysteine tag for peptide and protein labeling

(A) Reaction of C7 with functionalized peptides 86 and 87. (B) HPLC chromatogram depicting rapid and clean conversion of 86 to cysteine-labeled product 88 after 1 h. (C) Superior chemoselectivity of reagent C7 relative to maleimide 89 in the presence of cysteine-free peptide 87. D Reaction kinetics demonstrating the tunable functionalization of 86 with substituted arylsulfonyl bicyclobutane reagents.