Ugi/Aldol Sequence: Expeditious Entry to Several Families of Densely Substituted Nitrogen Heterocycles

摘要

Nitrogen-containing heterocyles represent the vast majority of drugs and biologically relevant molecules. Thus, one of the most investigated areas of present day synthetic organic chemistry is the development of novel and efficient strategies for the assembly of these valuable compounds. In this context, isocyanide-based multicomponent reactions (IMCRs) have met renewed interest because of their unmatched capability to rapidly generate molecular diversity and explore chemical space. In particular, the Ugi reaction (U-4CR) enjoys the lion's share of this methodology growth because of the extreme versatility it displays. As a matter of fact, although this condensation affords a linear peptide backbone, a plethora of strategies are available to rigidify Ugi adducts into more appealing druglike species. To date, Ugi/ Diels Alder, Ugi/Buchwald-Hartwig, Ugi/Heck, Ugi/ nucleophilic additions/substitutions, and Ugi/ring-closing metathesis pathways constitute the most well-established routes to gain access to a wide variety of cyclic scaffolds, and is in line with the post-condensation modification approach. Recently, more elaborated processes involving extensive manipulations of Ugi products to render natural productlike complex frameworks have also been reported. Within this blossoming and highly diversified arena of research, it is surprising to notice that aldol-type reactions have never been exploited. Indeed, such studies are reported herein and contain examples of four- and five-step, one-pot, post-MCR cascades, which creatively generate molecular diversity in exquisite non-obvious ways.