Cyclobutane and Cyclobutene Synthesis: Catalytic Enantioselective [2+2] Cycloadditions

Abstract

Cyclobutanes and cyclobutenes are important structural motifs found in numerous biologically significant molecules, and they are useful intermediates for chemical synthesis. Consequently, [2+2] cycloadditions to access cyclobutanes and cyclobutenes have been established to be particularly useful transformations. Within the last 10 years, an increase in the frequency of publications for catalytic enantioselective [2+2] cycloadditions has occurred. These reactions provide access to a wide array of enantiomerically enriched chemical diversity that was not previously attainable. Described in this review are the advances made in catalytic enantioselective [2+2] cycloadditions to access cyclobutanes and cyclobutenes.

Catalytic Asymmetric [3+1]‐Cycloaddition Reaction of Ylides with Electrophilic Metallo‐enolcarbene Intermediates

“…[8] Traditionally, [2+2]-cycloadditions with alkenes or alkynes have been the preferred synthetic route to cyclobutanes and cyclobutenes, but only recently has high enantiocontrol been achieved using chiral Lewis acid catalysis in these transformations. [9] [3+1]-Cycloaddition presents an attractive strategy for the construction of structurally diverse four-membered all-carbon rings; however, this approach has only recently been recognized and is underexploited. [6] A ring expansion catalytic methodology has been reported in which vinyldiazo esters and either another diazo compound [10a] or iminoiodinanes [10b] formed cyclobutenes or 2-azetines in what is a formal [3+1]-cycloaddition process (Scheme 1a).…”

Synthesis of 1,3-Substituted Cyclobutanes by Allenoate-Alkene [2 + 2] Cycloaddition

“…4 (2) In most cases, the 1,3-substituted cyclobutane core is achiral and therefore enantioselective synthesis is not required. 5,6 (3) 1,3-Substituted cyclobutanes have been shown to be isosteric with aromatic ring systems in molecules of pharmacological interest. 7–9 …”

Synthesis of (−)‐Hebelophyllene E: An Entry to Geminal Dimethyl‐Cyclobutanes by [2+2] Cycloaddition of Alkenes and Allenoates

“…Since previous methods to form geminal dimethylcyclobutanes in natural product synthesis [3,4] do not provide access to the key β-cyclobutylacetate motif, development of such a method was required to ensure a concise synthesis. We intended to form the unusual cis -fused cyclobutane core by enantioselective alkene–allenoate [2+2] cycloaddition [5–8] followed by diastereoselective reduction (Scheme 1a). …”