Catalytic dehydrogenative cross-coupling: forming carbon-carbon bonds by oxidizing two carbon-hydrogen bonds

The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

6.4. Polyynes 3123 6.5. Using R-Hydroxy Stannanes 3124 6.6. Using the Hurtley Reaction 3124 6.7. Using a Methylenation Reaction 3125 7. Conclusions and Future Prospects 3125 8. Uncommon Abbreviations 3125 9. Acknowledgments 3125 10. Note Added in Proof 3125 11. References 3126 * Authorstowhomcorrespondenceshouldbeaddressed(evano@chimie.uvsq.fr, nicolas.blanchard@uha.fr). † Université de Versailles Saint Quentin en Yvelines. ‡ Université de Haute-Alsace. Chem. Rev. 2008, 108, 3054–3131 3054

Copper-mediated coupling reactions and their applications in natural products and designed biomolecules synthesis.

Direct C-H transformation via iron catalysis.

The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates

The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates

The field of organic synthesis has made phenomenal advances in the past fifty years, yet chemists still struggle to design synthetic routes that will enable them to obtain sufficient quantities of complex molecules for biological and medical studies. Total synthesis is therefore increasingly focused on preparing natural products in the most efficient manner possible. Here we describe the preparative-scale, enantioselective, total syntheses of members of the hapalindole, fischerindole, welwitindolinone and ambiguine families, each constructed without the need for protecting groups—the use of such groups adds considerably to the cost and complexity of syntheses. As a consequence, molecules that have previously required twenty or more steps to synthesize racemically in milligram amounts can now be obtained as single enantiomers in significant quantities in ten steps or less. Through the extension of the general principles demonstrated here, it should be possible to access other complex molecular architectures without using protecting groups. Total synthesis, which involves the construction of complex organic molecules from simpler starting materials, has made remarkable progress in the past fifty years. Despite this, the demand for new synthetic routes capable of generating large natural products for further biological studies remains high. A team of chemists has now identified the abandonment of the routine use of 'protecting' groups in synthesis as a way of satisfying this demand. Protecting groups are often used to mask reactive parts of a molecule while chemical transformations take place elsewhere in that molecule. The potential of the 'unprotected' approach was demonstrated by the synthesis of several members of a large class of marine alkaloids without using a single protecting group. The procedure yields significant quantities of molecules that previously required 20 or more distinct chemical operations in 10 steps or fewer. Members of the hapalindole, fischerindole, welwitindolinone and ambiguine families were synthesized, each constructed without the use of a single protecting group. As a consequence, molecules that have previously required 20 or more steps to synthesize racemically in milligram amounts can now be procured as single enantiomers in significant quantities in 10 steps or less.

http://ccc.chem.pitt.edu/wipf/Courses/2320_07_files/JournalClub/15428.pdf

Total synthesis of marine natural products without using protecting groups

Full details are provided for the total synthesis of several members of the hapalindole family of natural products, including hapalindole Q, 12-epi-hapalindole D, 12-epi-fischerindole U, 12-epi-fischerindole G, 12-epi-fischerindole I, and welwitindolinone A. Use of the recently developed direct indole coupling enabled an efficient, practical, scalable, and protecting-group-free synthesis of each of these natural products. The original biosynthetic proposal is reviewed, and a revised biosynthetic hypothesis is suggested, validated by the above syntheses. The syntheses are also characterized by an adherence to the concept of “redox economy”. Analogous to “atom economy” or “step economy”, “redox economy” minimizes the superfluous redox manipulations within a synthesis; rather, the oxidation state of intermediates linearly and steadily increases throughout the course of the synthesis.

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Enantiospecific total synthesis of the hapalindoles, fischerindoles, and welwitindolinones via a redox economic approach.

The first total syntheses of welwitindolinone A and the most complex members of the fischerindole family, fischerindoles I and G, are reported. Highlights of these short, protecting-group-free syntheses include the application of the recently developed direct indole−carbonyl coupling, a simple approach for installing the quaternary center with neighboring chlorine atom, a regioselective dehydrogenation/dehydration cascade to access fischerindole I, and a remarkably facile oxidative ring contraction to construct welwitindolinone A. An alternative biogenetic hypothesis, whose accuracy is suggested by the success of the current syntheses, is also put forth for this alkaloid family.

/pdf/enantioselective-total-syntheses-of-welwitindolinone-a-and-1q8hx1qt03.pdf

Enantioselective Total Syntheses of Welwitindolinone A and Fischerindoles I and G

The invention of a method for the direct union of indoles and carbonyl compounds (ketones, amides, esters) is described. Using this new method, a short, enantioselective, gram-scale and protecting group-free synthetic entry to the fischerindole and hapalindole indole alkaloid family has been achieved from carvone and indole. Total syntheses of (+)-hapalindole Q and (-)-12-epi-fischerindole U isothiocyanate are reported. The absolute stereochemistry of the latter natural product has also been determined.

Direct coupling of indoles with carbonyl compounds: short, enantioselective, gram-scale synthetic entry into the hapalindole and fischerindole alkaloid families.

The conversion of an alcohol into a 1,3- diol via controlled, radical-mediated C-H functionalization has been demonstrated. The method entails nearly quantitative conversion of an alcohol to the corresponding N-substitutedcarbamate, followed by a variant of the Hofffman-Lδffler-Freytag reaction, cyclization, and hydrolysis to provide a 1,3-diol.

Jeremy M. Richter

Papers

Total synthesis of marine natural products without using protecting groups

Enantiospecific total synthesis of the hapalindoles, fischerindoles, and welwitindolinones via a redox economic approach.

Enantioselective Total Syntheses of Welwitindolinone A and Fischerindoles I and G

Direct coupling of indoles with carbonyl compounds: short, enantioselective, gram-scale synthetic entry into the hapalindole and fischerindole alkaloid families.

1,3-diol synthesis via controlled, radical-mediated c-h functionalization