ContentsI. Introduction 339 A. Oxidative Free-Radical Cyclizations 339 B. Mn(OAc) 3 340 II. Initiation 341 A. Mechanistic Considerations 341 B. Substrates 342 C. Oxidants 342 1. Mn(III) 342 2. Ce(IV), Fe(III), V(V), etc. 343 D. Further Oxidation of the Product 344 III. Termination 345 A. Oxidation by Mn(III) 345 B. Oxidation by Cu(OAc) 2 345 C. Chlorination 346 D. Addition to Nitriles and Carbon Monoxide 346 E. Hydrogen Abstraction 347 IV. Monocyclization 347 A. Radicals Derived from Acids 348 B. Radicals Derived from β-Keto Esters and β-Diketones That Lead to Cycloalkanones 348 1. R-Unsubstituted β-Keto Esters 348 2. R-Substituted β-Keto Esters 349 3. Diketones 351 C. Radicals Derived from β-Keto Esters, β-Diketones, and Malonate Esters That Lead to Cycloalkanes 351 D. Radicals Derived from β-Keto Esters, β-Keto Amides, and Malonate Esters That Lead to Lactones and Lactams 351 E. Additions to Aromatic Rings 352 V. Tandem Cyclizations 353 A. Additions to a Double Bond and then an Arene 353 B. Additions to Two Double Bonds 354 VI. Triple and Higher Cyclizations 356 VII. Asymmetric Induction 356 VIII. Annulations 357 IX. Oxidation of Ketones 358 X. Oxidation of Enol Ethers and Enamines 359 XI. Fragmentation−Cyclizations 360 XII. Synthetic Applications 361 XIII. Acknowledgments 362 XIV. References and Notes 362Barry B. Snider is a graduate of the University of Michigan (B.S.) and Harvard University (Ph.D.). After postdoctoral training at Columbia University, he joined the faculty of Princeton University. Since 1981 he has been at Brandeis University, where he is now Professor of Chemistry. He has been an Alfred P. Sloan fellow, a Dreyfus Teacher Scholar and an ACS Cope Scholar. His research interests are in the area of synthetic methods development and natural product synthesis. Current interests include oxidative free-radical cyclizations, Lewis acid-induced and -catalyzed reactions, ene reactions, and the synthesis of guanidine-containing natural products.

The reaction of an alkene having an allylic hydrogen (an "ene") with a compound containing a double or triple bond (enophile) to form a new bond with migration of the ene double bond and 1,5-hydrogen shift is referred to as the ene reaction (eq l).1 The ene

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To identify lipids with roles in tuberculosis disease, we systematically compared the lipid content of virulent Mycobacterium tuberculosis with the attenuated vaccine strain Mycobacterium bovis bacillus Calmette-Guérin. Comparative lipidomics analysis identified more than 1,000 molecular differences, including a previously unknown, Mycobacterium tuberculosis-specific lipid that is composed of a diterpene unit linked to adenosine. We established the complete structure of the natural product as 1-tuberculosinyladenosine (1-TbAd) using mass spectrometry and NMR spectroscopy. A screen for 1-TbAd mutants, complementation studies, and gene transfer identified Rv3378c as necessary for 1-TbAd biosynthesis. Whereas Rv3378c was previously thought to function as a phosphatase, these studies establish its role as a tuberculosinyl transferase and suggest a revised biosynthetic pathway for the sequential action of Rv3377c-Rv3378c. In agreement with this model, recombinant Rv3378c protein produced 1-TbAd, and its crystal structure revealed a cis-prenyl transferase fold with hydrophobic residues for isoprenoid binding and a second binding pocket suitable for the nucleoside substrate. The dual-substrate pocket distinguishes Rv3378c from classical cis-prenyl transferases, providing a unique model for the prenylation of diverse metabolites. Terpene nucleosides are rare in nature, and 1-TbAd is known only in Mycobacterium tuberculosis. Thus, this intersection of nucleoside and terpene pathways likely arose late in the evolution of the Mycobacterium tuberculosis complex; 1-TbAd serves as an abundant chemical marker of Mycobacterium tuberculosis, and the extracellular export of this amphipathic molecule likely accounts for the known virulence-promoting effects of the Rv3378c enzyme.TbAd | terpenyl transferase W ith a mortality rate exceeding 1.5 million deaths annually, Mycobacterium tuberculosis remains one of the world's most important pathogens (1). M. tuberculosis succeeds as a pathogen because of productive infection of the endosomal network of phagocytes. Its residence within the phagosome protects it from immune responses during its decades long infection cycle. However, intracellular survival depends on active inhibition of pH-dependent killing mechanisms, which occurs for M. tuberculosis but not species with low disease-causing potential (2). Intracellular survival is also enhanced by an unusually hydrophobic and multilayered protective cell envelope. Despite study of this pathogen for more than a century, the spectrum of natural lipids within M. tuberculosis membranes is not yet fully defined. For example, the products of many genes annotated as lipid synthases remain unknown (3), and mass spectrometry detects hundreds of ions that do not correspond to known lipids in the MycoMass and LipidDB databases (4, 5).To broadly compare the lipid profiles of virulent and avirulent mycobacteria, we took advantage of a recently validated metabolomics platform (4). This high performance liquid chromatography-mass spectrometry (HPLC-MS)...