Divergent, Strain-Release Reactions of Azabicyclo[1.1.0]butyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation.

The azetidine moiety is a privileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after. Towards this goal, we have found that azabicyclo[1.1.0]butyl carbinols, readily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain-release reactions upon N-activation. Treatment with trifluoroacetic anhydride or triflic anhydride triggered a semipinacol rearrangement to give keto 1,3,3-substituted azetidines. More than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups. Alternatively, treatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates which gave spiroepoxy azetidines upon treatment with base. The electronic nature of the activating agent dictates which pathway operates.

Strain Release of Donor-Acceptor Cyclopropyl Boronate Complexes.

The reactivity of boronate complexes which resemble donor-acceptor cyclopropanes is described. The enantioenriched cyclopropyl boronate complexes were shown to undergo concerted 1,2-metalate rearrangement/ring opening upon activation with a Lewis acid. This method provides atom-efficient access to optically active γ-carbonyl boronic esters in moderate to excellent yields with complete enantiospecificity. Furthermore, a three-component variant of the reaction was established through in situ alkylation, and the synthetic utility of the products as chiral building blocks was demonstrated.

Strain-Release-Driven Homologation of Boronic Esters: Application to the Modular Synthesis of Azetidines.

Azetidines are important motifs in medicinal chemistry, but there are a limited number of methods for their synthesis. Herein, we present a new method for their modular construction by exploiting the high ring strain associated with azabicyclo[1.1.0]butane. Generation of azabicyclo[1.1.0]butyl lithium followed by its trapping with a boronic ester gives an intermediate boronate complex which, upon N-protonation with acetic acid, undergoes 1,2-migration with cleavage of the central C-N bond to relieve ring strain. The methodology is applicable to primary, secondary, tertiary, aryl, and alkenyl boronic esters and occurs with complete stereospecificity. The homologated azetidinyl boronic esters can be further functionalized through reaction of the N-H azetidine, and through transformation of the boronic ester. The methodology was applied to a short, stereoselective synthesis of the azetidine-containing pharmaceutical, cobimetinib.