Asymmetric synthesis: From transition metals to organocatalysis

Umpolung in the allylation reaction is discussed with examples drawn from transition-metal-catalyzed allylic substitution (with the allylic unit acting as an electrophile) and Lewis base-catalyzed allylation of aldehydes with allyltrichlorosilane (with the allyl acting as a nucleophile). Iridium-catalyzed electrophilic allylation of O-nucleophiles has been employed in our new approach to C-nucleoside analogs, where the C-O bond (rather than C-C) was constructed stereospecifically. Variation of the absolute configuration in the starting segments allowed the synthesis of all four combinations of D/L-α/ β-ribosides. In the nucleophilic allylation of aldehydes, chiral pyridine-type N-oxide catalysts are presented, in particular QUINOX and METHOX, and the intriguing behavior of QUINOX is discussed. Here, the π-π interactions between the substrate aldehyde and the catalyst are suggested to rationalize the experimental observations. Good correlation between the calculated energies for the transition states and the experimentally observed enantioselectivities has been obtained

Lewis base-catalyzed reactions of SiX 3-based reagents with C=O, C=N (n → σ*)

Nucleophilic addition to carbonyl and heterocarbonyl compounds is the cornerstone of organic synthesis, highlighted by the classical examples of Grignard reactions, aldol condensation, and H4 reductions. However, when less reactive nucleophiles are employed, such as allyl-silane, activation is required. This chapter focuses on the activation of silicon reagents by chiral Lewis bases. The field of nucleophilic activation of the reagents 3/4 was pioneered by Sakurai and coworkers, who, in the late 1980s, reported on a highly diastereoselective allylation of aldehydes with allyltriha-losilanes 3 and 4 in the presence of stoichiometric amounts of CsF. If two molecules of the Lewis base are involved in the formation of the catalytically active species, or if a biden-tate catalyst is used, the reaction would proceed through the cationic hexacoordinate transition complex. The early phosphoramides exhibited modest enantioselectivity in the allylation reaction but played an important role in the mechanistic elucidation and development of the second generation of catalysts

Lewis bases as catalysts in the reduction of imines and ketones with silanes (n → σ*)

Silanes are widely recognized as efficient reagent for reduction of the carbonyl and imine functionality. In the case of alkyl- and aryl-silanes, the reaction requires catalysis by transition metal complexes or Lewis acids, which activate the electrophilic substrate. However, the enantioselectivity dropped dramatically in the case of the pyridyl derivative, presumably owing to the coordination of the pyridine nitrogen of the achiral substrate to Cl3SH, which thus competes with the chiral catalyst. Significantly, 105 proved to perform equally well in the reduction of both aromatic ketimines 1 and ketones 2, which place this catalyst among the rare systems that are applicable to both imines and ketones. The ready formation of esters of p-amino acids by reduction of the corresponding imines/enam-ines, which in turn can be prepared from the readily available p-keto esters, allowed an expedient synthesis of SCH48461, a potent, orally active inhibitor of cholesterol absorption

Organocatalysis with a fluorous tag: Asymmetric reduction of imines with trichlorosilane catalyzed by amino acid-derived formamides

Asymmetric reduction of ketimines 1 with trichlorosilane can be catalyzed by N-methylvaline-derived Lewis-basic formamides 3a−d with high enantioselectivity (≤95% ee) and low catalyst loading (1−5 mol %) at room temperature in toluene. Appending a fluorous tag, as in 5a−c, simplifies the isolation procedure, while preserving high enantioselectivity (≤92% ee)

Asymmetric reduction of imines with trichlorosilane, catalyzed by sigamide, an amino acid-derived formamide: scope and limitations

Enantioselective reduction of ketimines 6-10 With trichlorosilane can be catalyzed by the N-methyl valine-derived Lewis-basic formamide (S)-23 (Sigamide) with high enantioselectivity (<= 97% ee) land low catalyst loading, (1 - 5 mol %) at room temperature in toluene. The reaction is efficient with ketimines derived from aromatic amines (aniline and anisidine) and aromatic, heteroaromatic, conjugated, and even nonaromatic ketones 1-5, in which the steric difference between the alkyl groups R-1 and R-2 is sufficient. Simple nitrogen heteroaromatics (8a,b,d) exhibit low enantioselectivities due to the competing coordination of the reagent but increased steric hindrance in the Vicinity of the nitrogen (8c,e) results in a considerable improvement. Cyclic imines 32d-d exhibited low to modest enantioselectivities

Modular pyridine-type P,N-ligands derived from monoterpenes: Application in asymmetric Heck addition

Novel (diphenylphosphinophenyl)pyridine ligands (+)-8, (+)-15, (-)-21, and (-)-26 were synthesized from (-)-β-pinene, (+)-3-carene, (+)-2-carene, and (-)-α-pinene, respectively, via Kröhnke annulation as the key step, and shown to effect ≤88% ee in Heck addition (27→28). Ligands (+)-15 and (-)-21 are quasi-enantiomeric; ligands 8 and 26 can be prepared in both enantiomeric forms from (+)- and (-)-enantiomers of α- and β-pinene, respectively. © 2001 Elsevier Science Ltd

Palladium-catalyzed alkoxycarbonylation of terminal alkenes to produce α,β-unsaturated esters: the key role of acetonitrile as a ligand

A mild protocol has been developed for the Pd-catalyzed alkoxycarbonylation of terminal olefins to produce α,β-unsaturated esters with a wide range of substrates. Key features are the use of MeCN as solvent (and/or ligand) to control the reactivity of the intermediate Pd complexes and the combination of CO with O, which facilitates the Cu-mediated reoxidation of the Pd complex to Pd and prevents double carbonylation. Acetonitrile is the key! A mild protocol has been developed for the Pd-catalyzed alkoxycarbonylation of terminal olefins to produce α,β-unsaturated esters with a wide range of substrates (see scheme). Key features are the use of MeCN as a solvent (and/or ligand) to control the reactivity of the intermediate Pd complexes and the combination of CO with O, which facilitates the Cu-mediated reoxidation of Pd to Pd and prevents double carbonylation

Formamides derived from N-methyl amino acids serve as new chiral organocatalysts in the enantioselective reduction of aromatic ketimines with trichlorosilane

Asymmetric reduction of N-aryl ketimines 1a–k, 43, and 45 with trichlorosilane can be catalyzed by new N-methyl l-amino acid-derived Lewis-basic organocatalysts, such as the valine-derived bisamide 3d (10 mol%), in toluene at room temperature with high enantioselectivity (≤92% ee). The structure–reactivity investigation shows that the product configuration is controlled by the nature of the side chain of the catalyst scaffold (e.g., i-Pr vs Me, as in 3d and 6e), so that catalysts of the same absolute configuration may induce the formation of the opposite enantiomers of the product. Arene–arene interactions between the catalyst and the incoming imine appear to be the prerequisite for asymmetric induction. This metal-free, organocatalytic protocol is competitive with the traditional, metal-catalyzed methodology

Palladium-catalyzed stereoselective intramolecular oxidative amidation of alkenes in the synthesis of 1,3- and 1,4-amino alcohols and 1,3-diamines

An efficient and practical Pd-catalyzed intramolecular oxidative allylic amidation provides facile access to derivatives of 1,3- and 1,4-amino alcohols and 1,3-diamines. The method operates under mild reaction conditions (RT) with molecular oxygen (1 atm) as the sole reoxidant of Pd. Excellent diastereoselectivities were attained with substrates bearing a secondary stereogenic center Nitrogen in, hydrogen out: An efficient and practical Pd-catalyzed intramolecular oxidative allylic amidation provides facile access to derivatives of 1,3- and 1,4-amino alcohols and 1,3-diamines (see scheme). The method operates under mild reaction conditions (RT) with molecular oxygen (1 atm) as the sole reoxidant of Pd. Excellent diastereoselectivities were attained with substrates bearing a secondary stereogenic center