José C. González-Gómez

Visible-Light Photoredox Catalysis: Aza-Henry Reactions via C−H Functionalization

We report the application of visible-light photoredox catalysis for the formation of C-C bonds between tertiary N-arylamines and nitroalkanes via an oxidative aza-Henry reaction. In the presence of 1 mol % Ir(ppy)(2)(dtbbpy)PF(6), efficient coupling of nitroalkanes with in situ-generated iminium ions provides the desired products in up to 96% yield. Mechanistic studies suggest that reductive quenching of the Ir(3+) excited state by the tertiary amine leads to the ammonium radical cation, with subsequent catalyst turnover (Ir(2+) --> Ir(3+)) likely effected by atmospheric oxygen.

Diastereoselective allylation of carbonyl compounds and imines: application to the synthesis of natural products.

We thank the Spanish Ministerio de Ciencia e Innovacion (Grant Nos. CTQ2007-65218 and Consolider Ingenio 2010-CSD-2007-00006 and CTQ2011-24165), the Generalitat Valenciana (Grant No. PROMETEO/2009/039 and FEDER), and the University of Alicante for generous and continuous financial support.

Stereoselective α-Aminoallylation of Aldehydes with Chiral tert-Butanesulfinamides and Allyl Bromides†

The combination of an aldehyde, an allylic bromide, and tert-butanesulfinamide in the presence of indium metal and titanium tetraethoxide allows straightforward access to homoallylamine derivatives in high yields and stereoselectivities. Moreover, the synthetic utility of the enantioenriched homoallylamine derived from n-decanal was illustrated in a concise synthesis of (+)-isosolenopsin. In this context, similar homoallylamines has been recently used by other groups in the synthesis of naturally occurring alkaloids.

Efficiency in chemistry: from hydrogen autotransfer to multicomponent catalysis

A hydrogen autotransfer reaction has been applied to the α-alkylation of ketones, with primary alcohols as the electrophilic component, either under homogeneous (using a Ru complex as catalyst) or under heterogeneous (using Ni nanoparticles) conditions. This process is both very efficient (concerning atom economy) and ecologically friendly (water as the only by-product generated). On the other hand, three multicomponent reactions, namely, the Strecker reaction (without any catalyst), the aza-Sakurai process (catalyzed by ferrite), and the addition of in situ generated Zn enolates to chiral sulfinylimines (catalyzed by Cu), have proven to be very efficient in the generation of a diversity of polyfunctionalized molecules.

Photocatalytic Dehydrogenative Lactonization of 2-Arylbenzoic Acids

A metal-free dehydrogenative lactonization of 2-arylbenzoic acids at room temperature was developed. This work illustrates the first application of visible-light photoredox catalysis in the preparation of benzo-3,4-coumarins, an important structural motif in bioactive molecules. The combination of photocatalyst [Acr(+)-Mes] with (NH4)2S2O8 as a terminal oxidant provides an economical and environmentally benign entry to different substituted benzocoumarins. Preliminary mechanistic studies suggest that this reaction most likely occurs through a homolytic aromatic substitution pathway.

Stereoselective Synthesis of Azetidines and Pyrrolidines from N-tert-Butylsulfonyl(2-aminoalkyl)oxiranes†

Base-induced cyclization of enantiopure (2-aminoalkyl)oxiranes allowed the stereospecific formation of pyrrolidin-3-ols and/or 2-(hydroxymethyl)azetidines, depending on the reaction conditions. The oxidation of 2-(hydroxymethyl)azetidines led to azetidine-2-carboxylic acids in high yields.

Straightforward Access to Enantioenriched 2-Allylpiperidine: Application to the Synthesis of Alkaloids

An efficient stereocontrolled preparation of (2R,R(S))-2-allyl-(N-tert-butylsulfinyl)piperidine and its enantiomer is detailed. The sequence requires only two synthetic operations with one-column chromatography and is readily scaled up. The versatility of these chiral building blocks was exemplified by the total or formal synthesis of some natural and unnatural alkaloids.

Modular stereocontrolled assembly of R2Zn, cyclic enones and N-tert-butanesulfinyl imines.

The assembly of a wide range of dialkylzincs, cyclic enones, and chiral N-tert-butylsulfinyl imines in the presence of the appropriate phosphoramidite ligands allowed the formation of beta-amino ketones with three consecutive stereogenic centers in a stereocontrolled manner. The Baeyer-Villiger oxidation of the resulting amino ketones led to the corresponding aminolactones with excellent regio- and stereoselectivities.

Concise Total Synthesis and Stereochemical Analysis of Tetraponerines T3 and T4

An efficient stereocontrolled preparation of tetraponerines T3 and T4 is detailed. The sequence takes advantage of two consecutive stereoselective aminoallylations of appropriate aldehydes with chiral tert-butanesulfinamide and in situ generated allyl indium species. The absolute configuration of the carbon stereogenic center at the aminal moiety is thermodynamically controlled. This was ascertained on the basis of an exhaustive DFT configurational study of tetraponerines, which fulfils the lack of detailed structural information for these systems. It was found that the trans-transoid-configuration of the AB rings is the most stable geometry for T3 and T4. However, the C ring prefers a cis-configuration in T3 (ttc-T3) and a trans-fusion in T4 (ttt-T4). Regarding their dynamic behavior, low activation barriers were found by DFT calculations for the inversion of the nitrogen at the indolizidine framework, allowing rapid equilibration between the major configurations (ttc and ttt) in T3 and T4.

Integrated Ugi-based assembly of functionally, skeletally, and stereochemically diverse 1,4-benzodiazepin-2-ones.

A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.