In the past few decades, it has become clear that asymmetric catalysis is one of the most powerful methods for the construction of carbon-carbon as well as carbon-heteroatom bonds in a stereoselective manner. However, when structural complexity increases (i.e., all-carbon quaternary stereogenic center), the difficulty in reaching the desired adducts through asymmetric catalytic reactions leads to a single carbon-carbon bond-forming event per chemical step between two components. Issues of efficiency and convergence should therefore be addressed to avoid extraneous chemical steps. In this Perspective, we present approaches that tackle the stimulating problem of efficiency while answering interesting synthetic challenges. Ideally, if one could create all-carbon quaternary stereogenic centers via the creation of several new carbon-carbon bonds in an acyclic system and in a single-pot operation from simple precursors, it would certainly open new horizons toward solving the synthetic problems. Even more important for any further design, the presence of polyreactive intermediates in synthesis (bismetalated, carbenoid, and oxenoids species) becomes now an indispensable tool, as it creates consecutively the same number of carbon-carbon bonds as in a multi-step process, but in a single-pot operation.

The formation of all-carbon quaternary stereocentres in acyclic systems is one of the most difficult contemporary challenges in modern synthetic organic chemistry. Particularly challenging is the preparation of all-carbon quaternary stereocentres in aldol adducts; this difficulty is problematic because the aldol reaction represents one of the most valuable chemical transformations in organic synthesis. The main problem that limits the formation of these stereocentres is the absence of an efficient method of preparing stereodefined trisubstituted enolates in acyclic systems. Here we describe a different approach that involves the formation of two new stereogenic centres--including the all-carbon quaternary one--via a combined carbometalation-oxidation reaction of an organocuprate to give a stereodefined trisubstituted enolate. We use this method to generate a series of aldol and Mannich products from ynamides with excellent diastereomeric and enantiomeric ratios and moderate yields.

This protocol describes a new approach for the preparation of stereodefined trisubstituted chiral enolate species, avoiding conventional asymmetric enolization of carbonyl compounds. This protocol was developed as a single-flask synthetic sequence and therefore does not require isolation or purification of intermediate compounds. The sequence starts from a regioselective carbocupration reaction of readily accessible chiral ynamides; this is followed by oxidation of the generated vinylcuprate with a commonly available oxidizing reagent (tert-butyl hydroperoxide) in order to generate an enolate that completely retains its configuration. This synthetic protocol has been applied to the preparation of aldol and Mannich-type adducts. The procedure reported here requires a simple reaction setup commonly available in all synthetic laboratories and takes ∼6 h for completion and 2 h for isolation and purification. Final products are valuable diastereomerically and enantiomerically enriched building blocks for organic synthesis containing all-carbon quaternary stereocenters in acyclic systems.

The supramolecular chiral recognition between rac-2a and several structured RNA leads to a distinct (19)F NMR signal splitting. The (19)F NMR analysis of the diastereomeric pairs formed upon binding of this racemic probe delivers a topological footprint of the RNA. This phenomenon can be exploited to investigate dynamic events involving structural equilibria, as demonstrated in a melting experiment. This work provides a proof of concept that small fluorinated moderate binders can act as external probes of RNA structures.

In the last few decades we have witnessed the renaissance of zinc carbenoid in acyclic stereoselective synthesis. From the pioneering work of Simmons and Smith that led to a myriad of beautiful enantioselective cyclopropanations of alkenes, zinc carbenoid is again at the center of interest, but this time for the acyclic control of selectivity in allylation reactions. A straightforward method, utilizing the dual characteristics of zinc carbenoid serving both as an electrophile and as a nucleophile, has been recently developed for the preparation of various 3,3-disubstituted allylzinc species that react with various carbonyl and imine moieties to give homoallyl alcohols and amines, respectively, with very high diastereoselectivity. In a one-pot operation, three new carbon−carbon bonds as well as two new sp 3 stereogenic centers were formed, including the formation of the challenging all-carbon quaternary stereogenic centers.