Efficient and stereodivergent synthesis of unsaturated acyclic fragments bearing contiguous stereogenic elements

In the light of many transformative advances, organic synthesis is expected to allow chemists to create, transform and study the reactivity of any organic molecules, regardless of its complexity. Despite the ever-increasing synthetic toolbox available to practitioners, the perfect “atomic scale manipulation of matter for the synthesis of anything and everything” represents a never-ending and yet unmet challenge. Growing expectations to provide faster, more cost-efficient and highly selective transformations, however, set a high bar for modern chemical synthesis. Tending towards these ideals, research efforts have not only been focusing on the development of newly diverse and more efficient methodologies, but also on expanding the realm of new possibilities through original conceptual advances. For instance, introducing the notion of chemical space in organic synthesis has spurred chemists to explore more efficiently all the potential structural and geometric isomers of a given scaffold. Accordingly, the catalytic preparation of a three-dimensional molecular layout of a simple acyclic hydrocarbon skeleton that possesses several stereocenters from simple and readily available reagents still represents a vastly uncharted domain. Molecular complexity rapidly rises with the number of stereogenic elements, their degree of substitution and the additional presence of neighbouring functional groups. Furthermore, the elaboration of congested systems adds another level of complexity as exemplified by the difficulty to construct quaternary carbon stereocenters selectively. Although considerable progress in stereoselective synthesis has been made in the past few decades, general catalytic examples implemented for non-cyclic systems are still scarce, inherently due to the difficulty to discriminate between the different possible conformers of these flexible chains. One ambitious task would entail the selective preparation of all the possible isomers of a simple acyclic hydrocarbon motif that feature adjacent and congested stereogenic elements by means of a unified assembly-line approach, concomitantly allowing stereodivergency and diverse functionalization. Jeffrey Bruffaerts and David Pierrot from the research group of Prof. Marek successfully address the aforementioned issues in a recent publication published in Nature Chemistry. By taking advantage of the exergonic ring-opening reactions of strained cycles, a new protocol for the preparation combined with a metal-assisted and controlled ring-opening of the obtained functionalized cyclopropanes allowed an easy and straightforward access to stereodefined acyclic hydrocarbon fragments containing several adjacent sp2 and/or sp3 carbon stereogenic element(s) from simple commercially available alkynes.

The first asset of this approach is its efficiency as a simple alkyne is transformed into a highly strained motif enabling a series of energetically favoured transformations in a single-pot operation therefore minimizing the number of purification steps. The second asset is its versatility as polar moieties acted as a “molecular crane” to direct the approach of the organometallic entities, most structural and geometric isomers were therefore accessible by the starting molecular bricks’ interchangeability. Furthermore, owing to the diversity of the tolerated substituents, this methodology enables a near-exhaustive access to a broad family of structures which would be difficulty to access by other methods with those levels of selectivity, diversity, cost and time-efficiency. Owing to the presence of versatile chemical handles (aldehyde, alkene) which are accessible in an operationally simple manner, this study brings complex templates within the chemist’s hand reach, yet with great variability.

The study was published in the nature chemistry: https://www.nature.com/articles/s41557-018-0123-7