The desire for new synthetic methodologies for the rapid construction of enantiomerically pure substituted indole has been a fruitful driving force for chemical research in the last few years. This research line has produced a stunning array of enantioselective technologies either metal or organocatalyzed. This critical review documents the development of organocatalytic indole alkylation strategies, until the end of 2009 (127 references).

Dedicated to Professor Alfredo Ricci on the occasion of his 70th birthdayThe structural complexity and well-defined three-dimensional architecture of natural molecules are generally correlated with specificity of action and potentially useful biological properties.[1] This complexity has inspired generations of synthetic chemists to design novel enantioselective strategies for assembling challenging target structures and reproducing the rich structural diversity inherent in natural molecules. This symbiotic correlation between natural compounds synthesis and the discovery of effective asymmetric-generally catalytic [2] -technologies lies at the heart of the synthetic chemistry innovation.[3] Despite the substantial advances made thus far, the construction of highly strained polycyclic structures (particularly those that contain spiro-stereocenters) and the generation of all-carbon quaternary stereocenters still remain daunting targets for synthesis. [4,5] The spirocyclic oxindole core is featured in a number of natural products [6] as well as medicinally relevant compounds [7] (Figure 1), but its stereocontrolled synthesis, particularly installing the challenging spiro-quaternary stereocenter, poses a great synthetic problem. Only a few venerable asymmetric transformations, such as cycloaddition processes [8] or the intramolecular Heck reaction, [9] have proven suitable for achieving this challenging goal.Herein we show that asymmetric organocascade catalysis, [10] which exploits the ability of chiral amines to efficiently combine two modes of catalyst activation of carbonyl compounds (iminium and enamine catalysis) into one mechanism, [11] allows the direct, one-step synthesis of complex spirooxindolic cyclohexane derivatives; these products have three or four stereogenic carbon atoms and are obtained with extraordinary levels of stereocontrol starting from simple precursors. Specifically, we developed complementary organocatalytic multicomponent domino reactions based on two distinct organocatalysts, A and B, which efficiently activate carbonyl compounds such as ketones and aldehydes, respectively, toward multiple asymmetric transformations in a welldefined cascade sequence. Both strategies provide straightforward access to natural product inspired compound collections, [12] which would be difficult to synthesize by other enantioselective methods.

In recent years, organocatalysis has enhanced its importance as a tool for the synthesis of enantiomerically enriched compounds. Among the candidates for organocatalysis, the construction of asymmetric quaternary carbons is regarded as a challenging problem in organic synthesis. In particular, 3,3'-disubstituted oxindoles have one or more asymmetric quaternary carbon atoms and they represent a large family of bioactive compounds and synthetic derivatives that mimicry natural products. Therefore they are good targets for drug candidates and in the last two years many papers have appeared on organocatalytic methods for the synthesis of 3,3'-disubstituted oxindoles. Moreover, in the last few years 2-substituted and 2,2'-disubtituted 3-indolinones have also attracted the interest of chemists. This review aims to cover the literature on these topics from its origin to the end of 2011.

In spite of the many catalytic methodologies available for the asymmetric functionalization of carbonyl compounds at their α and β positions, little progress has been achieved in the enantioselective carbon–carbon bond formation γ to a carbonyl group. Here, we show that primary amine catalysis provides an efficient way to address this synthetic issue, promoting vinylogous nucleophilicity upon selective activation of unmodified cyclic α,β-unsaturated ketones. Specifically, we document the development of the unprecedented direct and vinylogous Michael addition of β-substituted cyclohexenone derivatives to nitroalkenes proceeding under dienamine catalysis. Besides enforcing high levels of diastereo- and enantioselectivity, chiral primary amine catalysts derived from natural cinchona alkaloids ensure complete γ-site selectivity: The resulting, highly functionalized vinylogous Michael adducts, having two stereocenters at the γ and δ positions, are synthesized with very high fidelity. Finally, we describe the extension of the dienamine catalysis-induced vinylogous nucleophilicity to the asymmetric γ-amination of cyclohexene carbaldehyde.

Abstract:The first catalytic asymmetric PictetSpengler reaction of isatins is presented. BINOLderived phosphoric acids were found to be competent catalysts for this transformation, giving challenging spirooxindole structures bearing a quaternary stereocentre with generally good results. The 1,2,3,4-tetrahydro-b-carboline products (spiroindol-