B

R = f-butylsilyi

TADDOL

'CO2f Bu

CH3COCl

NH2 O

Et3P

OH O

OH O

R = Ph 40%, 67% ee R = c-Hex 71%, 96% ee R = /-Pr 82%, 92% ee

OH OH

R = Ph 40%, 67% ee R = c-Hex 71%, 96% ee R = /-Pr 82%, 92% ee

OH OH

b^ySAn

Scheme 2.22 Hydrogen-bond assisted organocatalysis

enantioselective hydrocyanation of imines [138] (Scheme 2.22a) and opened the way to the development of other H-bond donors as versatile organocatalysts for mechanistically distinct reactions. In this context TADDOL and BINOL derivatives have been considered as chiral Bronsted acids acting as single H-bond donors and have found useful application in hetero Diels-Alder cycloadditions [139] as well as in Morita-Baylis-Hillman reaction to afford functionalised allyl alcohols [140] (Scheme 2.22b-c). A range of conjugate additions to nitroalkenes and Mannich reactions were successfully promoted by Cinchona-alkaloid or thiourea-based organocatalysts [141], the latter being active also in Pictet-Spengler reaction to give functionalised indoles as intermediates in the synthesis of alkaloids [142] (Scheme 2.22d).

NR 1

ClCH2CH2Cl2, 35 °C

Ar h

EtO2C +

CO2Et 43d

Scheme 2.23 Organocatalysis with strong Bronsted acids

BINOL-derived phosphoric acids 43 have been designed as strong Bronsted acid catalysts capable to activate substrates by way of protonation and induce efficient chirality transfer through their tight ion-pairing with the cationic intermediates so generated. Density functional calculations have supported this mechanism [143] and different addition reactions to imines [144] (Scheme 2.23a-c) as well as reductive amination of methyl ketones with amines [145] (Scheme 2.23d) have been optimized by tuning the 3,3'-substituents in binaphtyl scaffold of 43.

Dia- and enantio-selective epoxidation of a variety of di- and tri-substituted enals [146] (Scheme 2.24a) and transfer hydrogenation of b,b-unsaturated aldehydes [147] were efficiently performed in the presence of (R)-26 phosphate salts with an achiral ammonium cation. Such counteranion-directed strategy has been also applied to transition metal catalysis, that in this way can be effectively carried out without the need of chiral ligands in the metal complexes, and excellent results have been obtained in Pd-promoted a-allylation of aldehydes (Scheme 2.24b) for

Ar Ar

Ar CHO

Ar Ar

Lo O 11

fBuOOH

ArSsHO

Scheme 2.24 Counterion-directed catalysis

Ar the construction of carbon-quaternary stereogenic centers [148, 149] other than the above cited gold(I)-catalyzed intramolecular hydroamination of alienes.

Last advance in organocatalysis concerns the development of a novel activation mode, independently described by MacMillan's [150] and Sibi's [151] groups in 2007, based on the shift of the 2p-4p electron equilibrium between iminium and enamine species toward the formation of a transient 3p radical cation with a singly occupied molecular orbital (the SOMO intermediate), that can be trapped by non conventional coupling partners giving products otherwise difficult to achieve. The SOMO-activation of carbonyl-catalyst intermediates, operationally accomplished by including a one-electron oxidant in the catalytic system, has been mainly exploited for direct a-functionalization of aldehydes and ketones with p-rich olefins

[152] and in a sophisticated application to intermolecular polyene cyclization up to 6 new C-C bonds and 11 contiguous stereocenters were generated in a cascade process

[153] (Scheme 2.25). In order to overcome the required excess of chemical oxidant, phodoredox systems in catalytic amount have been recently proposed as alternative oxidant source under light excitation and a substantial improvement in SOMO-strategy is expected from coupling of these two classes of catalysts [154].

A quite specific group of organocatalysts has been developed for phase transfer catalysis, a methodology in which compounds with different solubility can react in biphasic aqueous-organic solvent mixtures in the presence of a catalyst able to provide great rate acceleration facilitating the transport of reagents or

Ph II

O Me

Ox Ph

t-Bu

SOMO-activation

56%, 92% ee

Scheme 2.25 a-Functionalization of aldehydes via SOMO-activation intermediates from the interfacial surface to the organic phase wherein the reaction really occurs. Phosphonium or quaternary ammonium salts with hydrophobic organic cations have been traditionally used as phase transfer catalysts since they promote the fast ion-exchange of metal enolates, generated from substrates with acidic protons at the interface with a basic aqueous solution, to form liphophilic onium enolates that are moved deep into the organic phase in which the reaction with an electrophilic partner takes place under the stereochemical control of chiral cation with concomitant regeneration of the catalyst (interfacial mechanism, Scheme 2.26b) [155]. Despite of the methodology has been dated since the end of 1960s, its application in asymmetric synthesis emerged later with the development and design optimization of Cinchona-alkaloid derived (44) [156] or N-spiro binaphtyl (45) quaternary ammonium salts as the most versatile families of phase transfer chiral catalysts [157]. Due to their well-defined chiral environments these catalysts, often active in remarkably low amount, provide effective shielding of one of the two enantiotopic faces of enolate anion so stereochemically controlling the enolate-electrophile reaction. The advantages of mild experimental conditions, increased selectivity, simplification in work-up procedures and applicability in large-scale preparations, make asymmetric phase-transfer reactions an attractive ''green'' alternative to homogeneous processes.

Alkylation of glycinate Schiff bases with alkyl halides under basic (usually KOH or NaOH) conditions has been widely exploited for the preparation of

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