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

A. Primary Alcohols as Nucleophiles 2931 B. Carboxylates as Nucleophiles 2931 C. Alkylations with Phenols 2932 IV. Nitrogen Nucleophiles in AAA Total Synthesis 2935 A. Alkylamines as Nucleophiles 2935 B. Azides as a Nucleophile 2936 C. Sulfonamide Nucleophiles 2937 D. Imide Nucleophiles 2938 E. Heterocyclic Amine Nucleophiles 2940 V. Sulfur Nucleophiles 2941 VI. Summary and Conclusions 2941 VII. Acknowledgment 2941 VIII. References 2942 I. Considerations for Enantioselective Allylic Alkylation

http://athena.uwindsor.ca/users/j/jlichaa/reference.nsf/54ef3e94e5fe816e85256d6e0063d208/10ff8b04ff3a317885256d88005720f6/$file/cr-2003-103-2921-trost-allylpd.pdf

Asymmetric transition-metal-catalyzed allylic alkylations: applications in total synthesis.

http://aether.cmi.ua.ac.be/artikels/Artikels%20Gitte/Artikels/Reviews/Trans.%20Metal.%20catal.%20reactions%20Chem.%20rev.%20042127.pdf

Transition-Metal-Catalyzed Reactions in Heterocyclic Synthesis

Metal-catalyzed enantioselective allylation, which involves the substitution of allylic metal intermediates with a diverse range of different nucleophiles or S(N)2'-type allylic substitution, leads to the formation of C-H, -C, -O, -N, -S, and other bonds with very high levels of asymmetric induction. The reaction may tolerate a broad range of functional groups and has been applied successfully to the synthesis of many natural products and new chiral compounds.

Metal-catalyzed enantioselective allylation in asymmetric synthesis.

An important first step in making organic reactions more environmentally benign by design requires processes that are, to a first approximation, simple additions with anything else needed only catalytically. Since so few of the existing reactions are additions, synthesis of complex molecules requires the development of new atom-economic methodology. The prospect for such developments is probed in the context of ruthenium-catalyzed reactions. Using mechanistic reasoning, over 20 new processes of varying complexity have been designed and implemented. While some involved oxidation−reduction processes, most involved C−C bond-forming reactions.

On Inventing Reactions for Atom Economy

The Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol allyl carbonates serves as an efficient strategy to construct the allylic C−O bond allowing access to chiral chromans in up to 98% ee. The effect of pH and the influence of olefin geometry, as well as substitution pattern on the ee and the absolute configuration of the chiral chromans were explored in detail. These observations suggest a mechanism involving the cyclization of the more reactive π-allyl palladium diastereomeric intermediate as the enantiodiscriminating step (Curtin−Hammett conditions). This methodology led to the enantioselective synthesis of the vitamin E core, the first enantioselective total synthesis of (+)-clusifoliol and (−)-siccanin, and the synthesis of an advanced intermediate toward (+)-rhododaurichromanic acid A.

Synthesis of chiral chromans by the Pd-catalyzed asymmetric allylic alkylation (AAA): scope, mechanism, and applications.

An examination of earlier reports of poor-to-modest results using Pd-catalyzed asymmetric allylic alkylations (AAA) to effect cyclization to form tetrasubstituted carbons reveals several novel factors that can influence this class of reactions. Thus, carboxylate has a major effect on such cyclizations wherein the ee increases from 14% ee favoring the S with no carboxylate to 84% ee favoring the R enantiomer in the presence of 1 equiv of carboxylate. Changing the double bond geometry from E to Z further increases the ee to 97%. Furthermore, the chiral catalyst that forms the R enantiomer with the E-alkene forms the S enantiomer with the Z alkene. In contrast to trisubstituted alkene substrates, disubstituted ones show a decrease in ee in going from the E to Z alkenes. The role of carboxylate appears to be a ligand to Pd during the catalytic cycle, a previously unsuspected phenomenon since such reactions are generally believed to involve π-allylpalladium cationic complexes. The dependence upon alkene geomet...

Unusual Effects in the Pd-Catalyzed Asymmetric Allylic Alkylations: Synthesis of Chiral Chromans

(-)-Siccanin (1), a natural product possessing significant antifungal properties, was synthesized enantioselectively via a biomimetic route. This synthetic route features two sequential radical cyclizations: a Ti(III)-mediated radical cyclization of epoxyolefin 48 to construct the B-ring, and a Suarez reaction to establish the tetrahyrofuran ring. Chiral chroman moiety of siccanin was prepared based on our recent development of the Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol trisubstituted allyl carbonates. Several other members of the siccanin family were also synthesized including siccanochromenes A (2), B (3), E (6), F (7), and the methyl ether of siccanochromene C (55). These studies may shed light on the biosynthesis of this novel family of compounds.

Biomimetic enantioselective total synthesis of (-)-siccanin via the Pd-catalyzed asymmetric allylic alkylation (AAA) and sequential radical cyclizations.

Jean-Philippe Surivet

Papers

Synthesis of chiral chromans by the Pd-catalyzed asymmetric allylic alkylation (AAA): scope, mechanism, and applications.

Unusual Effects in the Pd-Catalyzed Asymmetric Allylic Alkylations: Synthesis of Chiral Chromans

Biomimetic enantioselective total synthesis of (-)-siccanin via the Pd-catalyzed asymmetric allylic alkylation (AAA) and sequential radical cyclizations.

An Enantioselective Biomimetic Total Synthesis of (−)-Siccanin

Asymmetric Alkylation of Nitroalkanes