New strategies based on transition-metal catalysis or organocatalysis have provided new perspectives into the total synthesis of cyclobutane-containing natural products.

The enantioselective intramolecular α-arylation of cyclobutanones has been established by combining palladium and enamine catalyst systems. Two different enantioselective control strategies have been developed for cyclobutanone substrates bearing O- or N-tethered aryl bromides. Further synthetic applications are also reported.

Cyclobutane derivatives have been recognized as useful structural motifs in organic synthesis and drug design. With the revival of photochemistry, the enantioselective synthesis of cyclobutane derivatives using [2+2]-cycloadditions has garnered numerous attentions. On the other hand, enantioselective functionalization of preformed four-membered carbocycles is emerging as an important complementary approach to access chiral cyclobutane derivatives with versatile structural patterns. Herein, we summarize recent advances in this field from 2012. To avoid undesired C-C bond cleavage driven by strain-releasing, it is crucial to choose compatible methods for enantioselective functionalization and meanwhile preserving intact four-membered ring skeleton. Guided by calculated hydrogenation enthalpies, which are used to evaluate the strain energy of indicated C-C bond, a clear picture of the developed methodologies on functionalization of four-membered carbocycles combining the strain energy and enhanced reactivity is presented.

A copper‐catalyzed tandem process to generate chiral cyclobutene derivatives has been developed. It is based on an enantioselective conjugate addition or reduction of a cyclobutenone and sequential trapping with a chlorophosphate in a one‐pot process. These phosphates are stable under mildly acidic conditions and serve as good electrophiles in Negishi coupling reactions.

An asymmetric total synthesis of (+)-6-hydroxythiobinupharidine (1b) and (-)-6-hydroxythionuphlutine (2b), a set of hemiaminal containing dimeric sesquiterpenes isolated from yellow water lilies of the Nuphar genus, is described. The central bis-spirocyclic tetrahydrothiophene ring was forged through the Stevens rearrangement of a sulfonium ylide, generated in situ from the coupling of a copper-carbene with a spirocyclic thietane. This strategy diverges both from the proposed biosynthesis1 and previous syntheses of this family of alkaloids,2,3 all of which employ dimerization of symmetric monomers to form the aforementioned thiaspirane. The coupling of unsymmetrical monomers allowed access to the unsymmetrically oxidized product 2b for the first time.