The enantioselective synthesis of spirocycles has been a long time pursued dream for organic chemists. Since the first pioneering efforts of Tamao and coworkers in the enantioselective construction of spirosilanes, many efforts have been devoted to the development of new and promising asymmetric methodologies. Remarkably, with the advent of organocatalysis the number of methodologies has been highly increased. The aim of this tutorial review is to summarize the last trends and developments reported in the literature in the enantioselective synthesis of spirocompounds.

The enantioselective synthesis of spirocycles has long been pursued by organic chemists. Despite their unique 3D properties and presence in several natural products, the difficulty in their enantioselective synthesis makes them underrepresented in pharmaceutical libraries. Since the first pioneering reports of the enantioselective construction of spirosilanes by Tamao et al., significant effort has been devoted towards the development of new promising asymmetric methodologies. Remarkably, with the advent of organocatalysis, particularly over six years, the reported methodologies for the synthesis of spirocycles have increased exponentially. The aim of this review is to summarize the latest trends and developments in the enantioselective synthesis of spirocompounds during these last six years.

The development of new asymmetric methodologies that afford different structures in an enantioselective fashion is one of the most exciting goals for chemists nowadays. In this subject, lately, the use of sulfones has become a fast growing field. From the works of Tan and Shibata until the last works of Palomo, sulfones have demonstrated their versatility and power in organocatalytic asymmetric reactions. Moreover, the easy removal of sulfones with Mg or Hg/Na makes this group a perfect choice to afford easily naked alkyls. Remarkably, bissulfones can be used as nucleophiles or electrophiles, being vinyl sulfones excellent electrophiles, while bismethylensulfones derivatives such as fluoro are excellent nucleophiles. This double possibility has been studied by several research groups, leading to new methodologies that allow obtaining formally simple alkylation in an enantioselective fashion, by using organocatalysis. The aim of this tutorial review is to summarize the last trends in the use of sulfones in organocatalytic processes, giving a complete scenario of these new reagents.

Since the rediscovery of proline in 2000 as catalyst in aldol reaction by List, Barbas and Lerner and, soon after, the development of iminium catalysis by D. W. C. MacMillan, the emergence of organocatalysis as an important tool in organic synthesis is outstanding. During the last years, several research groups have worked in the development of new and powerful methodologies that allow us to build difficult molecules with high yields and enantioselectivities in a metal-free environment. Moreover, the possibility to join two or more organocatalytic reactions in one process has become one challenging goal for chemists, probably due to the costly protecting groups and time-consuming purification procedures after each synthetic step that are one of the common issues in organic synthesis. To circumvent these problems, tandem, domino, cascade or multicomponent organocatalytic reactions have been utilized for the efficient diastereo- and enantioselective construction of complex molecules from simple precursors in simple processes. For example, different tandem organocatalytic reactions such as cyclopropanation, aziridination, Michael-aldol, Michael-α-alkylation, etc. have been developed since 2006 with excellent yields and stereoselectivities. Herein, we describe the last trends and examples of organocatalytic domino reactions. This review aims to cover and discuss the current development of this fast growing field.

The synthesis of spiro compounds via a Michael–Michael-aldol reaction is reported. The reaction affords spirooxindole derivatives in good yields and in almost diastereo- and enantiopure form. Moreover, the reaction works with several heterocycles such as oxindoles, benzofuranones, pyrazolones or azlactones rendering the final spiro compounds in good yields and excellent stereoselectivities.