Fèlix Urpí

The copper-catalyzed aerobic oxidation of N-(2-arylacetyl)–1,3-oxazolidin-2-ones to the corresponding 2-oxo derivatives is described. The transformation is promoted by copper(II) acetate and 1,10-phenanthroline in DMSO at 30 °C and provides a wide range of 1,2-dicarbonyl compounds under mild reaction conditions. The method does not require bases or additional reagents, avoids prolonged heating, and proceeds through an operationally simple process with minimal waste generation. Eventually, the resulting α-keto imides can be readily converted into α-keto esters or amides and α-hydroxy derivatives.

We describe a direct and asymmetric aldol-like reaction between a wide range of N-acyl-1,3-oxazolidine-2-thiones and cobalt-protected propargylic acetals catalyzed by a chiral nickel(II) complex leading to syn β-alkoxy derivatives. This overcomes longstanding limitations associated with acetals from aliphatic aldehydes, selectively providing syn aldol adducts in excellent yields as single stereoisomers (dr >97:3, er up to >99:1). Furthermore, the cobalt fragment enables downstream intramolecular Pauson-Khand cyclizations, granting rapid access to densely functionalized bicyclic architectures.

Parallel asymmetric total syntheses of eliglustat and C2-epi-eliglustat are reported. Both approaches feature a common key step, which involves a stereocontrolled TMSOTf-mediated aldol-like reaction of azidoacetyl thioimides with dibenzyl acetals of aromatic aldehydes catalyzed by chiral nickel(II) complexes. It is worth noting that the structure of dibenzyl acetals plays a key role in the stereochemical outcome of some of these reactions, as supported by theoretical calculations. Overall, this strategy enables the independent manipulation of the amino and hydroxy functional groups and favors the isolation of enantiomerically pure products.

A new approach to the synthesis of all of the potential stereoisomers of β-alkoxy-α-amino acids derived from phenylalanine, tyrosine, tryptophan, and other β-aryl counterparts is reported. Such a method hinges on direct and asymmetric Lewis acid-mediated aldol-like reactions of N-azidoacetyl thioimides with dialkyl acetals from aromatic aldehydes catalyzed by chiral nickel(II) complexes. This produces at will both the corresponding syn and anti adducts, which can be smoothly converted into enantiomerically pure intermediates such as dipeptide fragments. In turn, computational calculations have unveiled clues for a better understanding of such a stereocontrolled carbon-carbon bond-forming transformation.

The direct reactions of a diverse range of N-acyl-1,3-oxazolidin-2-ones with TEMPO, catalyzed by copper(II) acetate and 4,7-dimethyl-1,10-phenanthroline without the need for any base, are herein described. These reactions afford the corresponding aminoxylated derivatives with high chemoselectivity and complete regioselectivity, achieving excellent yields under mild conditions. Further treatment of the resulting imides enables access to a variety of formally protected hydroxy compounds, which can be regarded as valuable synthetic intermediates. The efficient formal synthesis of isoproterenol highlights the potential of this methodology and sets the stage for further advancements in the catalytic chemistry of metal enolates.

A new approach to the synthesis of any of the potential stereoisomers of β-alkoxy-α-amino acids derived from phenylalanine, tyrosine, tryptophan, and other β-aryl counterparts is reported. Such a method hinges on direct and asymmetric Lewis acid–mediated aldol-like reactions of N-azidoacetyl thioimides with dialkyl acetals from aromatic aldehydes catalyzed by chiral nickel(II) complexes. This produces at will both the corresponding syn and anti adducts, which can be smoothly converted into enantiomerically pure intermediates, such as dipeptide fragments. In turn, computational calculations have unveiled the clues for a better understanding of such a stereocontrolled carbon–carbon bond–forming transformation.

Direct and stereodivergent Michael additions of N‐acyl 1,3‐thiazinane‐2‐thiones to α,β‐unsaturated aldehydes catalyzed by chiral nickel(II) complexes are reported. The reactions proceed with a remarkable regio‐, diastereo‐, and enantioselectivity, so access to any of the four potential Michael stereoisomers is granted through the appropriate choice of the chiral ligand of the nickel(II) complex. Simple removal of the heterocyclic scaffold furnishes a wide array of either syn or anti enantiomerically pure derivatives, which can be exploited for the asymmetric synthesis of biologically active compounds, as demonstrated in a new approach to tapentadol. In turn, a mechanism, based on theoretical calculations, is proposed to account for the stereochemical outcome of these transformations.

Direct and stereodivergent Michael additions of N‐acyl 1,3‐thiazinane‐2‐thiones to α,β‐unsaturated aldehydes catalyzed by chiral nickel(II) complexes are reported. The reactions proceed with a remarkable regio‐, diastereo‐, and enantioselectivity, so access to any of the four potential Michael stereoisomers is granted through the appropriate choice of the chiral ligand of the nickel(II) complex. Simple removal of the heterocyclic scaffold furnishes a wide array of either syn or anti enantiomerically pure derivatives, which can be exploited for the asymmetric synthesis of biologically active compounds, as demonstrated in a new approach to tapentadol. In turn, a mechanism, based on theoretical calculations, is proposed to account for the stereochemical outcome of these transformations.

Oxocarbenium cations are key intermediates for the stereocontrolled construction of carbon–carbon bonds. In particular, we have developed a wide range of stereoselective aldol-like processes that take advantage of the high reactivity of the oxocarbenium species arising from acetals, glycals, and orthoesters with metal enolates. This Account describes the development and optimization of such processes, together with other significant contributions, with a particular emphasis on their application to the synthesis of natural products.1 Introduction2 Substrate-Controlled Processes2.1 Additions to Acyclic Acetals2.2 Additions to Cyclic Acetals3 Chiral-Auxiliary-Based Processes3.1 Additions to Acyclic Acetals3.2 Additions to Cyclic Acetals and Glycals4 Chiral-Catalysis-Based Processes4.1 Organocatalysis4.2 Metal Catalysis5 Conclusions

A direct and asymmetric syn-aldol reaction of N-acyl-1,3-oxazinane-2-thiones with dialkyl acetals from aromatic acetals in the presence of 2-5 mol % [DTBM-SEGPHOS]NiCl₂, TMSOTf, and lutidine has been developed. It has been established that the oxazinanethione heterocycle, used for the first time as a scaffold in asymmetric carbon-carbon bond-forming reactions, can be smoothly removed to give access to a variety of enantiomerically pure compounds with high synthetic value.