Guillem Valero

Enantioselective Organocatalytic Synthesis of Fluorinated Molecules

The enantioselective synthesis of fluorinated molecules has drawn much attention within the chemical community due to its unique stereoelectronic properties. The main aim of this review is to cover the most important organocatalytic enantioselective methodologies to obtain them. The review is divided into three parts: first, the direct introduction of a fluorine atom studied in the early 2000s. Second, the later use of Michael reactions to introduce fluorine-containing synthons. Finally, the simultaneously-developed trifluoromethylation reactions, giving the catalysts, mechanisms and reagents that have been used.

Highly Enantio‐ and Diastereoselective Organocatalytic Desymmetrization of Prochiral Cyclohexanones by Simple Direct Aldol Reaction Catalyzed by Proline

Panacea for aldol desymmetrizations: We describe an easy entry for the desymmetrization of 4-substituted-cyclohexanones catalyzed by proline, using as cocatalysts different hydrogen-bonding donors (see scheme), which dramatically improves the catalytic efficiency of proline in desymmetrization reactions.

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.

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.

A Closer Look at Spontaneous Mirror Symmetry Breaking in Aldol Reactions

The aldol reaction between acetone and 4-nitrobenzaldehyde run in the nominal absence of any enantioselective catalyst was monitored by chiral HPLC with the aid of an internal standard. The collected data show the presence of a detectable initial enantiomeric excess of the aldol product in the early stages of the reaction in about 50 % of the experiments. Only a small fraction of the reaction contained the non-racemic aldol product after 24 h. This temporary emergence of natural optical activity could be the signature of a coupled reaction network that leads to a spontaneous mirror-symmetry-breaking process, which originates at very low conversions (i.e., strongly depends on events taking place at the very first stages of the process). The reaction is not autocatalytic in the aldol product, which rules out a simple Frank-type reaction network as the source of the observed symmetry breaking. On the other hand, the isolation and characterisation of a double-aldol adduct suggested a reaction network that involved both indirect autocatalysis and indirect mutual inhibition between the enantiomers of the reaction product.

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.

Cooperative Effects Between Arginine and Glutamic Acid in the Amino Acid‐Catalyzed Aldol Reaction

Catalysis of the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde by mixtures of L-Arg and of L-Glu in wet dimethyl sulfoxide (DMSO) takes place with higher enantioselectivity (up to a 7-fold enhancement in the anti-aldol for the 1:1 mixture) than that observed when either L-Glu or L-Arg alone are used as the catalysts. These results can be explained by the formation of a catalytically active hydrogen-bonded complex between both amino acids, and demonstrate the possibility of positive cooperative effects in catalysis by two different α-amino acids. Chirality 28:599-605, 2016.

Searching for Spontaneous Mirror-Symmetry Breaking in Organoautocatalytic Reactions

Autocatalytic chemical reactions are assumed to have played a key role in the emergence of life, and asymmetric autocatalytic reactions in particular appear to be the key to understanding the fundamental question of the origin of biological homochirality in prebiotic chemistry. The possibility of chemical reactions that starting from achiral reagents can lead to an essentially homochiral product by amplification of a very tiny enantiomerical imbalance was predicted by Frank in 1953, in a model that postulates mutual antagonism between both enantiomers of the autocatalyst. The experimental realization of this concept appeared to be restricted to the asymmetric autocatalytic dialkylzinc addition to pirimidylcarbaldehydes discovered by Soai and co-workers, but recent reports point to the possibility of spontaneous mirror-symmetry breaking (SMSB) and of asymmetric autocatalysis in organocatalytic reactions. We summarize herein our recent experimental work on the existence of organoautocatalysis and SMSB in aldol and in Mannich reactions.