Multicomponent reactions (MCRs) receive increasing attention because they address both diversity and complexity in organic synthesis. Thus, in principle diverse sets of relatively complex structures can be generated from simple starting materials in a single reaction step. The ever increasing need for optically pure compounds for pharmaceutical and agricultural applications as well as for catalysis promotes the development of asymmetric multicomponent reactions. In recent years, asymmetric multicomponent reactions have been applied to the total synthesis of various enantiopure natural products and commercial drugs, reducing the number of required reaction steps significantly. Although many developments in diastereoselective MCRs have been reported, the field of catalytic enantioselective MCRs has just started to blossom. This critical review describes developments in both diastereoselective and catalytic enantioselective multicomponent reactions since 2004. Significantly broadened scopes, new techniques, more environmentally benign methods and entirely novel MCRs reflect the increasingly inventive paths that synthetic chemist follow in this field. Until recently, enantioselective transition metal-catalyzed MCRs represented the majority of catalytic enantioselective MCRs. However, metal contamination is highly undesirable for drug synthesis. The emergence of organocatalysis greatly influences the quest for new asymmetric MCRs.

Recent developments in asymmetric multicomponent reactions.

"Comprehensive Heterocyclic Chemistry" was published in 1984 and is now available on CD-ROM.

Comprehensive heterocyclic chemistry on CD-ROM

We report an efficient method for the alkylation of γ-C(sp3)–H bonds of picolinamide-protected aliphatic amine substrates with primary alkyl iodides via palladium catalysis. Ag2CO3 and dibenzyl phosphate, (BnO)2PO2H, are critical promoters of this reaction. These reactions provide a convenient and straightforward method for the preparation of high-value N-containing products from readily available amine and alkyl iodide precursors.

Palladium-Catalyzed Picolinamide-Directed Alkylation of Unactivated C(sp3)–H Bonds with Alkyl Iodides

The asymmetric hydrogenation of aromatic and heteroaromatic compounds arguably presents one of the most attractive methods for the synthesis of six-membered cyclic compounds. In recent years, a number of promising stereoselective methods for the asymmetric hydrogenation of pyridines and related heterocycles have been reported.

Asymmetric hydrogenation of aromatic compounds

A new asymmetric entry of the 1,2-aza-Friedel−Crafts reaction catalyzed by a chiral phosphoric acid is described. The present reaction has provided an atom-economical route to furan-2-ylamine derivatives in a highly enantioselective fashion. The synthetic utility of these products was displayed by oxidative cleavage of the furan ring (aza-Achmatowicz reaction) to form a 1,4-dicarbonyl compound that could be further derivatized to a chiral γ-butenolid.

Organocatalytic Asymmetric Aza-Friedel−Crafts Alkylation of Furan

Recent advances in the synthesis of piperidones and piperidines

A short synthesis of the parp inhibitor 2-(4-trifluoro-methylphenyl)benzimidazole-4-carboxamide (NU1077)

The present invention relates to novel substituted piperidine derivatives of formula (1), stereoisomers thereof, and pharmaceutically acceptable salts thereof which are useful as histamine receptor antagonists and tachykinin receptor antagonist. Such antagonists are useful in the treatment of allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; asthma; bronchitis; and emesis.

Substituted 4-(1H-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases

Recent Advances in the Synthesis of Piperidones and Piperidines

The present invention relates to novel substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamide derivatives of the formula ##STR1## stereoisomers thereof, and pharmaceutically acceptable salts thereof which are useful as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; asthma; bronchitis; and emesis.

John M. Kane

Papers

Recent advances in the synthesis of piperidones and piperidines

A short synthesis of the parp inhibitor 2-(4-trifluoro-methylphenyl)benzimidazole-4-carboxamide (NU1077)

Substituted 4-(1H-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases

Recent Advances in the Synthesis of Piperidones and Piperidines

Substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl) benzamides useful for the treatment of allergic diseases