Hélio Faustino

Axially chiral triazoloisoquinolin-3-ylidene ligands in gold(I)-catalyzed asymmetric intermolecular (4 + 2) cycloadditions of allenamides and dienes.

The first highly enantioselective intermolecular (4 + 2) cycloaddition between allenes and dienes is reported. The reaction provides good yields of optically active cyclohexenes featuring diverse substitution patterns and up to three stereocenters. Key to the success of the process is the use of newly designed axially chiral N-heterocyclic carbene-gold catalysts.

Enantioselective gold(I)-catalyzed intramolecular (4+3) cycloadditions of allenedienes.

The (4+3) cycloaddition of conjugated dienes and allylic cations represents a highly valuable strategy for the preparation of seven-membered carbocycles. Indeed, this type of annulation has been successfully used as a key step in the synthesis of several complex natural products and advanced intermediates. 3] However, very important challenges, such as the development of catalytic versions that work with readily available precursors, and principally, the implementation of enantioselective variants, remain to be satisfactorily developed. Indeed, we are aware of only two isolated reports on catalytic enantioselective (4+3) cycloadditions of allylic cations, and both deal with the intermolecular annulation of furans. We have recently reported a new type of (4+3) cycloaddition strategy based on the platinumor gold-catalyzed intramolecular reaction of allene-tethered dienes such as 1 (Scheme 1). The reaction is particularly efficient when catalyzed by the cationic gold(I) complex Au1/AgSbF6, which features a s-donating N-heterocyclic carbene ligand. 9] In the course of these studies, we also discovered that allenedienes 1, when dialkylated at the distal position of the allene (R, R’= alkyl), preferentially provide (4+2) cycloadducts of type 3, as long as the gold catalyst incorporates a pacidic ligand such as a phosphite or a phosphoramidite. Additionally, we have found that when using suitable chiral phosphoramidite/gold(I) catalysts (e.g. (R,R,R)-Au3–Au5) the cycloadditions proceed in an enantioselective manner to provide optically active bicyclic compounds 3. Mechanistic studies suggest that both types of products, 2 and 3, arise from the common carbenic species II, itself coming from the (4+3) cycloaddition of 1 via allylic cation intermediate I (Scheme 1). Species II might then evolve either by ring contraction (1,2-alkyl migration, route b) or by a standard 1,2H shift (route a). Although the phosphite type of ligands seem to favor the ring contraction process over the 1,2-H shift, theoretical data suggest that the activation barriers for both processes are not so different. Therefore, we reasoned that chiral phosphoramidite/gold catalysts might be also capable of inducing (4+3) annulations, provided that the ring-contraction route (route b) could be slightly deactivated. Herein, we demonstrate the viability of this approach by reporting a highly enantioselective intramolecular (4+3) cycloaddition of allenedienes 1. The reactions are promoted by the chiral phosphoramidite/gold(I) catalyst (R,R,R)-Au5/ AgSbF6 and provide a straightforward route to optically active, synthetically relevant bicyclo[5.3.0]decadiene and bicyclo[5.4.0]undecadiene skeletons. To the best of our knowledge the transformation represents the first example of an intramolecular, highly enantioselective (4C + 3C) cycloaddition. Previous studies in the group suggested that reducing the number of substituents at the allene terminus of 1 (from two to one) has a drastic negative effect on the formation of cyclohexene adducts 3, while cycloheptenyl products 2 and 2 can still be satisfactorily obtained. Therefore, we initially Scheme 1. Ptand Au-catalyzed cycloadditions of allenedienes 1.

Gold(I)-catalyzed intermolecular (4 + 2) cycloaddition of allenamides and acyclic dienes

A new type of intermolecular (4 + 2) cycloaddition, based on a gold-catalyzed reaction between allenamides and acyclic conjugated dienes, is reported. The annulation, which fails under standard Diels–Alder conditions, provides a straight entry to a variety of differently substituted cyclohexenes, and takes place with excellent regio- and diastereoselectivity.

Mechanistic intricacies of gold-catalyzed intermolecular cycloadditions between allenamides and dienes

The mechanism of the gold-catalyzed intermolecular cycloaddition between allenamides and 1,3-dienes has been explored by means of a combined experimental and computational approach. The formation of the major [4+2] cycloaddition products can be explained by invoking different pathways, the preferred ones being determined by the nature of the diene (electron neutral vs. electron rich) and the type of the gold catalyst (AuCl vs. [IPrAu](+), IPr=1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene). Therefore, in reactions catalyzed by AuCl, electron-neutral dienes favor a concerted [4+3] cycloaddition followed by a ring contraction event, whereas electron-rich dienes prefer a stepwise cationic pathway to give the same type of formal [4+2] products. On the other hand, the theoretical data suggest that by using a cationic gold catalyst, such as [IPrAuCl]/AgSbF6, the mechanism involves a direct [4+2] cycloaddition between the diene and the gold-activated allenamide. The theoretical data are also consistent with the observed regioselectivity as well as with the high selectivity towards the formation of the enamide products with a Z configuration. Finally, our data also explain the formation of the minor [2+2] products that are obtained in certain cases.

Gold(I)-Catalyzed Intermolecular Cycloaddition of Allenamides with α,β-Unsaturated Hydrazones: Efficient Access to Highly Substituted Cyclobutanes

α,β-Unsaturated N,N-dialkyl hydrazones undergo a mild [2 + 2] cycloaddition to allenamides when treated with a suitable gold catalyst. The method, which represents the first application of N,N-dialkyl hydrazones in gold catalysis, is compatible with a wide variety of substituents at the alkenyl moiety of the hydrazone component, proceeds with excellent levels of regio- and diastereoselectivity, and provides densely substituted cyclobutanes with good to excellent yields.

Ruthenium-Catalyzed Azide–Thioalkyne Cycloadditions in Aqueous Media: A Mild, Orthogonal, and Biocompatible Chemical Ligation

Abstract The development of efficient metal‐promoted bioorthogonal ligations remains as a major scientific challenge. Demonstrated herein is that azides undergo efficient and regioselective room‐temperature annulations with thioalkynes in aqueous milieu when treated with catalytic amounts of a suitable ruthenium complex. The reaction is compatible with different biomolecules, and can be carried out in complex aqueous mixtures such as phosphate buffered saline, cell lysates, fetal bovine serum, and even living bacteria (E. coli). Importantly, the reaction is mutually compatible with the classical CuAAC.

Bioconjugation with Maleimides: A useful Tool for Chemical Biology

Maleimide chemistry stands out in the bioconjugation toolbox by virtue of its synthetic accessibility, excellent reactivity, and practicability. The second-generation of clinically approved antibody-drug conjugates (ADC) and much of the current ADC pipeline in clinical trials contain the maleimide linkage. However, thiosuccinimide linkages are now known to be less robust than once thought, and ergo, are correlated with suboptimal pharmacodynamics, pharmacokinetics, and safety profiles in some ADC constructs. Rational design of novel generations of maleimides and maleimide-type reagents have been reported to address the shortcomings of classical maleimides, allowing for the formation of robust bioconjugate linkages. This review highlights the main strategies for rational reagent design that have allowed irreversible bioconjugations in cysteines, reversible labelling strategies and disulfide re-bridging.