Nucleosides, Nucleotides, and Nucleic Acids, 25:1309–1333, 2006 Copyright C  Taylor & Francis Group, LLC ISSN: 1525-7770 print / 1532-2335 online DOI: 10.1080/15257770600917013 A REVIEW: SYNTHESIS OF ARYL C -GLYCOSIDES VIA THE HECK COUPLING REACTION Kevin W. Wellington and Steven A. Benner ✷ Foundation for Applied Molecular Evolution, Gainesville, Florida, USA ✷ In this article, we focus on the synthesis of aryl C-glycosides via Heck coupling. It is organized based on the type of structures used in the assembly of the C-glycosides (also called C-nucleosides) with the following subsections: pyrimidine C-nucleosides, purine C-nucleosides, and monocyclic, bicyclic, and tetracyclic C-nucleosides. The reagents and conditions used for conducting the Heck coupling reactions are discussed. The subsequent conversion of the Heck products to the corresponding target molecules and the application of the target molecules are also described. INTRODUCTION It has been over 3 decades since Pitha et al. [1] reported the synthesis of the first molecule that might be called an oligonucleotide analog, in 1970. It is difficult to remember that at that time, RNA sequencing was difficult, and no practical DNA sequencing technology of any type was available. As a consequence, this early oligonucleotide analog was built by simply polymerizing an acrylic derivative of thymine. With no defined sequence, the analog was not a starting point for research. Times have changed greatly. Today, 12 independently replicating nucle- obases are available as independently replicatable entities. Oligonucleotides containing nonstandard nucleobases are commercial products made on the millimole scale. Over 400,000 people have their health care improved using diagnostics tools that incorporate portions of an artificially expanded genetic alphabet. [2,3] The utility of oligonucleotides containing nonstandard nucleobases and other base-modified oligonucleotide analogs has driven the need to synthe- size these. In part, the target structures are constrained by our increasingly detailed understanding of the roles of various parts of the nucleic acid molecule. [4] For example, the repeating charge delivered by the phosphate Received 27 April 2006; accepted 13 June 2006. Addreess correspondence to Steven A. Benner, Foundation for Applied Molecular Evolution, PO Box 13174, Gainesville, FL 32604. E-mail: sbenner@ffame.org 1309