Strategies for the Synthesis of Selenocysteine Derivatives

β-Seleno-α-amino acids, known as selenocysteine (Sec) derivatives, have emerged as important targets because of their role in chemical biology, not only as part of selenoproteins with important redox properties, but also because of their activities as antivirals or metabolites effective in inhibiting carcinogenesis. In addition, there is a demand for this type of compounds due to their use in native chemical ligation to construct large peptides. Therefore, this review summarizes the various synthetic methods that have been published to construct Sec derivatives. Most of them involve the generation of the C-Se bond by nucleophilic substitution reactions, but other reactions such as radical or multicomponent strategies are also reported. Of particular importance is the Se-Michael addition of Se-nucleophiles to chiral bicyclic dehydroalanines, in which the stereogenic centre is generated under complete stereocontrol. 1 Introduction 2 Previously reviewed synthesis of Sec 3 Retrosynthesis of Sec derivatives 4 Sec derivatives by nucleophilic substitutions 5 Sec derivatives by radical processes 6 Sec derivatives by 1,4-conjugate additions

Enantioselective a,d-Difunctionalization of Dienes Initiated by Rh-Catalyzed Conjugate Addition

Metal-catalyzed enantioselective conjugate additions are highly reliable methods for stereoselective synthesis, however multi-component reactions that are initiated by conjugate arylation of acyclic p-systems are rare. These processes generally proceed with poor diastereoselectivity while requiring basic, moisture sensitive organometallic nucleophiles. Here we show that Rh-catalysts supported by a tetrafluorobenzobarrelene ligand (Ph-tfb) enable the enantio-, diastereo-, and Z-selective a,d-difunctionalization of electron-deficient 1,3-dienes with organoboronic acid nucleophiles and aldehyde electrophiles to generate Z-homoallylic alcohols with three stereocenters. The reaction accommodates diene substrates activated by ester, amide, ketone, or aromatic groups and can be used to couple aryl, alkenyl, or alkyl aldehydes. Diastereoselective functionalization of the Z-olefin unit in the addition products allow for the generation of compounds with five stereocenters in high dr and ee. Mechanistic studies suggest aldehyde allylrhodation is the rate determining step, and unlike reactions of analogous Rh-enolates, the Rh-allyl species generated by d-arylation undergoes aldehyde trapping rather than protonolysis, even when water is present as a co-solvent. These findings should have broader implications in the use of privileged metal-catalyzed conjugate addition reactions as entry points towards the preparation of acyclic molecules containing non-adjacent stereocenters.

Enantioselective a,d-Difunctionalization of Dienes Initiated by Rh-Catalyzed Conjugate Addition

Metal-catalyzed enantioselective conjugate additions are highly reliable methods for stereoselective synthesis, however multi-component reactions that are initiated by conjugate arylation of acyclic p-systems are rare. These processes generally proceed with poor diastereoselectivity while requiring basic, moisture sensitive organometallic nucleophiles. Here we show that Rh-catalysts supported by a tetrafluorobenzobarrelene ligand (Ph-tfb) enable the enantio-, diastereo-, and Z-selective a,d-difunctionalization of electron-deficient 1,3-dienes with organoboronic acid nucleophiles and aldehyde electrophiles to generate Z-homoallylic alcohols with three stereocenters. The reaction accommodates diene substrates activated by ester, amide, ketone, or aromatic groups and can be used to couple aryl, alkenyl, or alkyl aldehydes. Diastereoselective functionalization of the Z-olefin unit in the addition products allow for the generation of compounds with five stereocenters in high dr and ee. Mechanistic studies suggest aldehyde allylrhodation is the rate determining step, and unlike reactions of analogous Rh-enolates, the Rh-allyl species generated by d-arylation undergoes aldehyde trapping rather than protonolysis, even when water is present as a co-solvent. These findings should have broader implications in the use of privileged metal-catalyzed conjugate addition reactions as entry points towards the preparation of acyclic molecules containing non-adjacent stereocenters.

Non-Covalent Interactions in Enantioselective Organocatalysis: Theoretical and Mechanistic Studies of Reactions Mediated by Dual H-Bond Donors, Bifunctional Squaramides, Thioureas and Related Catalysts

Chiral bifunctional dual H-bond donor catalysts have become one of the pillars of organocatalysis. They include squaramide, thiosquaramide, thiourea, urea, and even selenourea-based catalysts combined with chiral amines, cinchona alkaloids, sulfides, phosphines and more. They can promote several types of reactions affording products in very high yields and excellent stereoselectivities in many cases: conjugate additions, cycloadditions, the aldol and Henry reactions, the Morita–Baylis–Hilman reaction, even cascade reactions, among others. The desire to understand mechanisms and the quest for the origins of stereoselectivity, in attempts to find guidelines for developing more efficient catalysts for new transformations, has promoted many mechanistic and theoretical studies. In this review, we survey the literature published in this area since 2015.