Multistep synthetic routes to eight structurally diverse and medicinally relevant targets were planned autonomously by the Chematica computer program, which combines expert chemical knowledge with network-search and artificialintelligence algorithms. All of the proposed syntheses were successfully executed in the laboratory and offer substantial yield improvements and cost savings over previous approaches or provide the first documented route to a given target. These results provide the long-awaited validation of a computer program in practically relevant synthetic design.

A one-pot multicomponent procedure for the synthesis of highly functionalized pyrrolidine rings through a domino 2-aza-Cope-[3+2] dipolar cycloaddition sequence has been demonstrated. This protocol was found to be both high yielding and stereoselective for the endo-cycloadduct.The pyrrolidine ring represents a prevalent scaffold for many compounds of pharmaceutical interest as well as a structural element common to the Amaryllidaceae and Erythrina alkaloids. 1 The development of mild, efficient, and operationally simple methods for their construction continues to warrant interest. As chemical synthesis places an ever-increasing emphasis on concise molecular assembly, processes that rapidly assemble complex structures in a stereocontrolled fashion are highly desirable. Toward these ends, multicomponent reactions have played an important role. 2 The orchestration of two or more distinct chemical events involving multiple components permits a magnification of structural complexity in a minimal number of synthetic steps. 3 In the context of heterocyclic chemistry, strategic extensions of the 2-aza-Cope rearrangement could potentially meet these criteria. Specifically, the merging of the 2-aza-Cope rearrangement with a [3+2] dipolar cycloaddition reaction could provide new and more concise routes to a variety of pyrrolidine-containing targets.The 2-aza-Cope rearrangement affords imine or iminium products which could in principle be used directly for additional carbon-carbon bond forming events. A classic example of this strategy is well illustrated by Overman's aza-Cope-Mannich reaction (Scheme 1). 4 In this powerful variant, a charge-accelerated cationic 2-aza-Cope rearrangement affords an iminium ion having an enol moiety correctly positioned for Mannich cyclization. The utility of this process has been amply demonstrated by Overman 5 and others 6 in many elegant total syntheses. Bennett and others have used a 2-aza-Cope-iminium ion solvolysis protocol to prepare allylglycine derivatives. 7 * stephen.waters@uvm.edu . Supporting Information Available:Experimental procedures, characterization data, and NMR spectra for all new compounds. X-ray crystallographic information for 2-allyl proline 4a. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2011 September 3. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptInspired by these advancements, we took interest in developing conceptually new unions of the 2-aza-Cope rearrangement with other carbon-carbon bond forming reactions. We first envisioned that the 2-aza-Cope rearrangement could be used to prepare azomethine ylide precursors for direct use in [3+2] dipolar cycloadditions. Such a strategy would capitalize on the considerable bond-reorganization properties of the Cope rearrangement as well as the diversity and facility of azomethine ylide cycloaddition. Condensation of a homoallylic amine with a glyoxylate ester would ...

The stereoselective synthesis of a diverse set of functionalized indolizidine systems has been accomplished through the aza-Prins cyclization of 2-allylpyrrolidines. The condensation of aldehydes onto 2-allylpyrrolidines yields iminium ions that undergo highly diastereoselective aza-Prins cyclization, producing up to two stereogenic centers and two new rings in one step.

A concise entry to functionalized indolizidine scaffolds through a domino 2-aza-Cope-[3+2] dipolar cycloaddition and Pauson–Khand [2+2+1] cyclization has been accomplished. The process was conducted under mild conditions to afford diverse indolizidine systems as single diastereomers in good overall yields.