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

Abstract

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.

Functionalized azetidines via visible light-enabled aza Paternò-Büchi reactions

“…In comparison, formation of the four-membered azetidines is hampered as it requires access to conformation 10b , which is higher in energy due to unfavorable eclipsing interactions 12 . Thus, strategies that proceed upon strain release of azabicyclobutanes ( 5 ) as three-membered ring analogs were developed as viable alternatives for the synthesis of azetidines 13–18 . In addition, orthogonal strategies for azetidine synthesis were developed that rely on the reduction of more readily accessible β -lactam precursors ( 6 ) 10,19,20 .…”

Chiral donor–acceptor azetines as powerful reactants for synthesis of amino acid derivatives

“…A classic approach to nucleophile coupling is the retro-Claisen reaction of β-ketoesters 6 that would require the construction of 2-carboxylate substituted 3-azetidinones, but the basic methods available for their ring-closing formation are the same as those desired for their ring-opening which is favored by ring strain 7–10 . Although one example of N -Cbz protected 2-carboxylate substituted 3-azetidinones is reported, its synthetic utility has not been pursued due to its inherent instability to nucleophilic ring opening 11 .…”

Flow Technology for Telescoped Generation, Lithiation and Electrophilic (C3) Functionalization of Highly Strained 1‐Azabicyclo[1.1.0]butanes

“… a) Synthesis and use of strained 1‐azabicyclo[1.1.0]butanes, b) generation and use of lithiated derivatives (ref. [5]) and c) proposed flow approach.…”