In contrast to the very large number of special methods applicable to syntheses in the heterocyclic series, relatively few general methods are available. The 1,3-dipolar addition offers a remarkably wide range of utility in the synthesis of five-membered heterocycles. Here the “1,3-dipole”, which can only be represented by zwitterionic octet resonance structures, combines in a cycloaddition with a multiple bond system – the “dipolarophile” – to form an uncharged five-membered ring. Although numerous individual examples of this reaction were known, some even back in the nineteenth century, fruitful development of this synthetic principle has been achieved only in recent years.

1,3-Dipolar Cycloadditions. Past and Future†

In studying the evolution of organic chemistry and grasping its essence, one comes quickly to the conclusion that no other type of reaction plays as large a role in shaping this domain of science than carbon-carbon bond-forming reactions. The Grignard, Diels-Alder, and Wittig reactions are but three prominent examples of such processes, and are among those which have undeniably exercised decisive roles in the last century in the emergence of chemical synthesis as we know it today. In the last quarter of the 20th century, a new family of carbon-carbon bond-forming reactions based on transition-metal catalysts evolved as powerful tools in synthesis. Among them, the palladium-catalyzed cross-coupling reactions are the most prominent. In this Review, highlights of a number of selected syntheses are discussed. The examples chosen demonstrate the enormous power of these processes in the art of total synthesis and underscore their future potential in chemical synthesis.

Palladium-catalyzed cross-coupling reactions in total synthesis.

Small-molecule H-bond donors in asymmetric catalysis.

Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C-F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.

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Introduction of Fluorine and Fluorine-Containing Functional Groups

A new iron(III) halide-promoted aza-Prins cyclization between γ,δ-unsaturated tosylamines and aldehydes provides six-membered azacycles in good to excellent yields. The process is based on the consecutive generation of γ-unsaturated-iminium ion and further nucleophilic attack by the unsaturated carbon−carbon bond. Homoallyl tosylamine leads to trans-2-alkyl-4-halo-1-tosylpiperidine as the major isomer. In addition, the alkyne aza-Prins cyclization between homopropargyl tosylamine and aldehydes gives 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines as the only cyclic products. The piperidine ring is widely distributed throughout Nature, e.g., in alkaloids,1 and is an important scaffold for drug discovery, being the core of many pharmaceutically significant compounds.2,3 The syntheses of these type of compounds have been extensively studied in the development of new drugs containing six-membered-ring heterocycles.4 Reactions between N-acyliminium ions and nucleophiles, also described as amidoalkylation or Mannich-type condensations, have been frequently used to introduce substituents at the R-carbon of an amine.5 There are several examples that involve an intramolecular attack of a nucleophilic olefin into an iminium cation for the construction of a heterocyclic ring system.6 Traditionally, the use of hemiaminals or their derivatives as precursors of N-acyliminium intermediates has been a common two-step strategy in these reactions.6a Among this type of cyclization is the aza-Prins cyclization,7 which uses alkenes as intramolecular nucleophile. However, cy† X-ray analysis. E-mail address: malopez@ull.es. (1) (a) Fodor, G. B.; Colasanti, B. Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 23, pp 1-90. (b) Baliah, V.; Jeyarama, R.; Chandrasekaran, L. Chem. ReV. 1983, 83, 379-423. (2) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679-3681. (3) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893-930. (4) Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729 and references therein. (5) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3187- 3856 and references therein. (6) (a) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, O., Heathcock, C. H., Eds.; Pergamon: New York, 1991; Vol. 2, pp 1047-1081. (b) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-4416. (7) (a) Dobbs, A. P.; Guesne, S. J. J.; Hursthouse, M. B.; Coles, S. J. Synlett 2003, 11, 1740-1742. (b) Dobbs, A. P.; Guesne, S. J. J.; Martinove, S.; Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880-7883. (c) Hanessian, S.; Tremblay, M.; Petersen, F. W. J. Am. Chem. Soc. 2004, 126, 6064-6071 and references therein. (d) Dobbs, A. P.; Guesne, S. J. Synlett 2005, 13, 2101-2103. ORGANIC

Iron-Catalyzed Reactions in Organic Synthesis

A facile method for the pinacol rearrangement of phenylethanediol derivatives by the use of 2-chloropyrimidinium salt

In the presence of a catalytic amount of trityl salts, silyl enol ethers of thioesters stereoselectively react with α,β-unsaturated ketones to afford the Michael adducts in high yields. 5-Oxocarboxylic acid ester derivatives, useful synthetic precursors of various naturally occurring compounds, are stereoselectively obtained by this procedure.

The Highly Stereoselective Michael Reaction of α,β-Unsaturated Ketones with Silyl Enol Ethers of Thioesters Catalyzed by Trityl Salts. A Facile Stereoselective Synthesis of 5-Oxocarboxylic Acid Ester Derivatives.

In the presence of a catalytic amount of diphenylboryl triflate, cyclic meso-dicarboxylic anhydrides are esterified by diphenylboric ester of (R)-2-methoxy-1-phenylethanol in a highly stereoselective manner, and, after the treatment with diazomethane, the chiral diesters are obtained with high diastereomeric excess.

Highly Efficient Asymmetric Esterification of Cyclic meso-Dicarboxylic Anhydrides Catalyzed by Diphenylboryl Triflate.

In the presence of a catalytic amount of several trityl salts, 2,3,5-tri-O-benzyl-D-ribofuranose smoothly reacted with alcohols to give various β-ribofuranosides in high yields with high stereoselectivity while reversed stereoselectivity was observed in the coexistence of lithium perchlolate.

Trityl Salt Catalyzed Stereoselective Glycosylation of Alcohols with 1- Hydroxyribofuranose.

Treatment of S-(2-pyridyl) aromatic thioates, readily derived from aromatic carboxylic acids, with bis(1,5-cyclooctadiene)nickel [Ni(COD)2] under mild conditions afforded symmetrical aromatic keton...

Teruaki Mukaiyama

Papers

A facile method for the pinacol rearrangement of phenylethanediol derivatives by the use of 2-chloropyrimidinium salt

The Highly Stereoselective Michael Reaction of α,β-Unsaturated Ketones with Silyl Enol Ethers of Thioesters Catalyzed by Trityl Salts. A Facile Stereoselective Synthesis of 5-Oxocarboxylic Acid Ester Derivatives.

Highly Efficient Asymmetric Esterification of Cyclic meso-Dicarboxylic Anhydrides Catalyzed by Diphenylboryl Triflate.

Trityl Salt Catalyzed Stereoselective Glycosylation of Alcohols with 1- Hydroxyribofuranose.

A new method for the preparation of symmetrical aromatic ketones from aromatic carboxylic acids