Andrea-Nekane R. Alba

Organocatalytic Domino Reactions

Since the rediscovery of proline in 2000 as catalyst in aldol reaction by List, Barbas and Lerner and, soon after, the development of iminium catalysis by D. W. C. MacMillan, the emergence of organocatalysis as an important tool in organic synthesis is outstanding. During the last years, several research groups have worked in the development of new and powerful methodologies that allow us to build difficult molecules with high yields and enantioselectivities in a metal-free environment. Moreover, the possibility to join two or more organocatalytic reactions in one process has become one challenging goal for chemists, probably due to the costly protecting groups and time-consuming purification procedures after each synthetic step that are one of the common issues in organic synthesis. To circumvent these problems, tandem, domino, cascade or multicomponent organocatalytic reactions have been utilized for the efficient diastereo- and enantioselective construction of complex molecules from simple precursors in simple processes. For example, different tandem organocatalytic reactions such as cyclopropanation, aziridination, Michael-aldol, Michael-?-alkylation, etc. have been developed since 2006 with excellent yields and stereoselectivities. Herein, we describe the last trends and examples of organocatalytic domino reactions. This review aims to cover and discuss the current development of this fast growing field.

Enantioselective Organocatalytic Addition of Oxazolones to 1,1-Bis(phenylsulfonyl)ethylene: A Convenient Asymmetric Synthesis of Quaternary α-Amino Acids

A new, easy, and highly enantioselective method for the synthesis of quaternary alpha-alkyl-alpha-amino acids based on organocatalysis is reported. The addition of oxazolones to 1,1-bis(phenylsulfonyl)ethylene is efficiently catalyzed by simple chiral bases or thioureas. The reaction affords alpha,alpha-disubstituted alpha-amino acid derivatives with complete C4 regioselectivity and with excellent yields and enantioselectivities. This methodology is complementary to previously reported enantioselective approaches to quaternary alpha-amino acids and allows the synthesis of alpha-phenyl-alpha-alkyl-alpha-amino acids and alpha-tert-butyl-alpha-alkyl-alpha-amino acids. It has distinct advantages in terms of operational simplicity, enviromentally friendly conditions, and suitability for large-scale reactions.

Formal Highly Enantioselective Organocatalytic Addition of Fluoromethyl Anion to α,β-Unsaturated Aldehydes

Symmetric fluoromethylation made easy: a highly enantioselective fluoromethyl addition to ?,?-unsaturated aldehydes is described (see scheme). The synthesis of chiral fluorinated blocks, including ?-fluoro-?-aminoalcohol derivatives is disclosed.

Enantioselective Organocatalytic Addition of Azlactones to Maleimides: A Highly Stereocontrolled Entry to 2,2‐Disubstituted‐2H‐oxazol‐5‐ones

The first highly diastereo- and enantioselective organocatalytic synthesis of 2,2-disubstituted-2H-oxazol-5-ones is described. The addition of oxazolones to maleimides is promoted by bifunctional thiourea catalysts, which afford the corresponding 2,2-disubstituted-2H-oxazol-5-ones with total regio- and stereocontrol.

Formal Highly Enantioselective Organocatalytic Addition of Alkyl Anions to α,β‐Unsaturated Aldehydes: Application to the Synthesis of Isotope‐Enantiomers

For the first time, organocatalytic addition of masked alkyl chains to ?,?-unsaturated aldehydes is reported (see scheme). The addition of bisphenylsulfonylmethane takes place in high yields and with excellent enantioselectivities. Furthermore, this methodology allows the synthesis of isotope-enantiomers.

The Holy Grail of Organocatalysis: Intermolecular α‐Alkylation of Aldehydes

Organocatalytic intermolecular ?-alkylation has been accomplished. The groups of Melchiorre and Cozzi have recently reported the realization of this long-time goal in organocatalysis, by the crucial use of stabilized carbocations. Alkylated products are obtained in good yields and with moderate to good enantioselectivities.

Kinetic resolution: a powerful tool for the synthesis of planar-chiral ferrocenes.

Since the serendipitous discovery of ferrocene by Pauson and Kealy in 1951, it has become one of the most important structures in Organic Chemistry. Lately, kinetic resolution has emerged as a useful tool for the synthesis of planar chiral ferrocenes. This review aims to cover and discuss the development of this topic.

Asymmetric organocatalytic Michael addition of azlactones to cis-1,2-bis(phenylsulfonyl)ethene. A simple entry to quaternary α-amino acids

Azlactones react with 1,2-bis(phenylsulfonyl)ethene under catalysis by simple chiral thioureas, affording α,α-disubstituted α-amino acid derivatives in good yields and in moderate to good enantioselectivities.

Enantioselective addition of oxazolones to maleimides. An easy entry to quaternary aminoacids

The catalytic enantioselective addition of 2-tert-butyl-4-aryl-1,3-oxazol-5-ones to maleimides is reported. The addition takes place exclusively at the C-4 position of the oxazolone ring, giving access to quaternary amino acid derivatives. The reaction is catalyzed by readily available chiral bases such as (DHQD)2PYR, rendering the final compounds in good yields and with moderate to good diastereo- and enantioselectivities. When the C-4-substituent of the 2-tert-butyl-oxazolone is an alkyl group, the regioisomeric C-2 addition product is also obtained.