Current Organic Synthesis - Volume 7, Issue 4, 2010

Jetze J. Tepe was born in Gouda, The Netherlands in 1968. He received his BS degree in 1992 from Jacksonville University, Florida and was awarded a PhD from the University of Virginia in 1998 where he worked with Prof. Timothy L. Macdonald on the design and synthesis of topoisomerase II inhibitors as potential chemotherapeutic agents. Following his PhD studies, he joined the laboratory of Prof. Robert M. Williams as a post-doctoral researcher, where he worked on the total synthesis and biological evaluation of various pyrrolizidine alkaloids and their analogues. In 2000, he joined the faculty at Michigan State University as an Assistant Professor and was promoted to Associate Professor in 2006. Research in the Tepe lab has been focused on the development of new heterocyclic reactions, cycloaddition reactions, and the synthesis and biological evaluation of novel heterocyclic natural products and analogues thereof. In 2003, he received the American Cancer Research Scholar award and in 2007 a Senior Award from the Multiple Myeloma Research Foundation. Dr Tepe is currently an editorial advisory board member of Current Bioactive Compounds. He is the co-Founder and Vice President of Research of TCH Pharmaceuticals (Ann Arbor, MI) and has served in various capacities including consultant and scientific advisory board member of several biotechnology corporations.

With increasing demands on atom economy, reaction efficiency, stereoselectivity, streamlined total syntheses, as well as product diversity, new developments in cycloaddition reactions are excelling at an ever increasing pace. Cycloaddition reactions are an efficient means to install multiple stereocenters and rapidly construct core skeletal structures of complex products. It is therefore not surprising that cycloaddition reactions have found great use in the efficient assembly of numerous diverse natural products. This Hot Topic Issue highlights some of the more recent, creative and elegant applications of dipolar cycloadditions in natural product synthesis. The four review articles selected for this Hot Topic Issue are devoted to the recent advances in cycloaddition reactions and their applications as key reactions in the total synthesis of a diverse set of natural products. i) Burrell and Coldham describe the total syntheses of multiple diverse natural products using ylide 1,3-dipoles in intramolecular cycloaddition reactions with π-systems. This comprehensive review discusses the application of azomethine ylides, carbonyl ylides, nitrones and nitronates, nitrooxides and azides in the total syntheses of over thirty different classes of natural products. ii) France and Phun review the use Rh(II) catalyzed 1,3-dipolar cycloadditions of carbonyl ylides as a powerful method to generate mono-and polycyclic heterocycles in an enantioselective fashion. The tandem Rh(II)- catalyzed carbonyl ylide/1,3-dipolar cycloaddition reactions have shown tremendous utility in the asymmetric synthesis of various natural products. iii) Garner and Kaniskan describe the use of the asymmetric [C+NC+CC] coupling reaction and its elegant application in the formal total synthesis of cyanocycline A. These stereoselective multi-component azomethine ylide cycloaddition reactions produce highly functionalized pyrrolidines in a highly predictable and controlled fashion. iv) Hsung and co-workers describe the recent developments in aza-[3+3] annulations. This unique approach to bond formation provides pivotal piperidinyl heterocycles that represent a prevalent structural motif in many biologically relevant natural products. As guest editor for COS for this special issue I would like to acknowledge and thank the contributors for their efforts to provide these timely reviews.

This review describes ylide 1,3-dipoles in cycloaddition reactions for the synthesis (and formal synthesis) of natural products. Examples using azomethine ylides, carbonyl ylides, nitrones, nitronates, nitrile oxides and azides are provided. These lead to a diverse array of heterocyclic products. Intramolecular cycloaddition provides two new rings in one step and hence an efficient entry to complex target compounds.

The Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides derived from diazocarbonyl compounds is one of the most powerful methods for the synthesis of mono- and polycyclic heterocycles. Recently, there has been a growing interest in the development of enantioselective variants of this protocol and the direct application in asymmetric total synthesis. Herein, we discuss recent advances in this field in the context of the type of chiral method used for stereoselective synthesis with particular emphasis on the levels of asymmetric induction.

Development of the asymmetric [C+NC+CC] coupling reaction is described. This reaction assembles aldehyde (C), amine (NC), and alkene (CC) components in a predictable and controlled fashion to give highly functionalized pyrrolidines. The utility of the asymmetric [C+NC+CC] coupling reaction is demonstrated by its application to an efficient formal total synthesis of cyanocycline A.

An aza-[3 + 3] annulation or formal cycloaddition strategy for constructing complex heterocycles, chiefly alkaloids, is reviewed here. This annulation involves a Knoevenagel-type condensation of α,β-unsaturated iminium salts with vinylogous amides or urethanes followed by a 6π-electron electrocyclic ring-closure. Both the inter- and intramolecular aza-annulation pathways illustrated here constitute a stepwise formal [3 + 3] cycloaddition in which two σ-bonds are formed in addition to a new stereogenic center adjacent to the heteroatom. This review describes our total synthesis efforts in the last ten years to unequivocally demonstrate that this aza-[3 + 3] annulation can serve as a powerful approach and a unified strategy in alkaloid synthesis.