Stereospecific Alkenylidene Homologation of Organoboronates via Concerted Nucleophilic Substitution Reaction

Core Concepts

A general and stereospecific method for the alkenylidene homologation of diverse organoboronates via a concerted nucleophilic substitution (SNV) reaction, enabling the iterative incorporation of multiple alkenylidene units to construct cross-conjugated polyenes.

Abstract

The content describes a new organic chemistry transformation called the concerted nucleophilic substitution (SNV) reaction, which enables the stereospecific alkenylidene homologation of organoboronates. This method allows for the iterative incorporation of multiple alkenylidene units, leading to the construction of cross-conjugated polyenes that are otherwise challenging to prepare. The key highlights are: Concerted SNV reactions, which involve the backside attack of a nucleophile on an sp2 vinyl electrophile, are rare and limited to carefully designed substrates. The authors have developed a general and stereospecific method for alkenylidene homologation of diverse organoboronates via an accelerated SNV reaction, facilitated by a proposed strain-release mechanism in metallated complexes. This approach enables the iterative incorporation of multiple alkenylidene units, giving access to cross-conjugated polyenes that are difficult to prepare using other methods. The method has also been demonstrated in the synthesis of bioactive compounds containing multi-substituted alkenes. Computational studies suggest an unusual SN2-like concerted pathway promoted by diminishing steric strain in the square planar transition state, which explains the high efficiency and stereoinversive feature of this metallate SNV reaction.

Stats

Concerted nucleophilic substitution, known as SN2 reaction, is a fundamental organic transformation used in synthesis to introduce new functional groups and construct carbon−carbon and carbon−heteroatom bonds. SN2 reactions typically involve backside attack of a nucleophile to the σ* orbital of a C(sp3)−X bond (X= halogen or other leaving group), resulting in complete inversion of a stereocenter. The corresponding stereoinvertive nucleophilic substitution on electronically unbiased sp2 vinyl electrophiles, namely concerted SNV(σ) reaction, is much rarer and so far, limited to carefully designed substrates mostly in ring-forming processes.

Quotes

"Here we show that concerted SNV reactions can be accelerated by a proposed strain-release mechanism in metallated complexes, leading to the development of a general and stereospecific alkenylidene homologation of diverse organoboronates." "This method enables the iterative incorporation of multiple alkenylidene units, giving cross-conjugated polyenes that are challenging to prepare otherwise." "Computational studies suggest an unusual SN2-like concerted pathway promoted by diminishing steric strain in the square planar transition state, which explains the high efficiency and stereoinversive feature of this metallate SNV reaction."

Key Insights Distilled From

Stereospecific alkenylidene homologation of organoboronates by SNV reaction - Nature

by Miao Chen,Ch... at www.nature.com 05-23-2024

https://www.nature.com/articles/s41586-024-07579-7

Deeper Inquiries

How can this stereospecific alkenylidene homologation method be further expanded to incorporate other types of functional groups or building blocks beyond organoboronates?

The stereospecific alkenylidene homologation method described in the context can be expanded to incorporate other functional groups or building blocks by exploring the reactivity of different nucleophiles towards the metallated complexes. By understanding the electronic and steric effects of various nucleophiles, researchers can design substrates that are compatible with the proposed strain-release mechanism. Additionally, modifying the ligands on the metal center can influence the reactivity and selectivity of the SNV reaction, allowing for the incorporation of a broader range of functional groups. Furthermore, investigating the impact of different solvents and reaction conditions on the reaction outcome can provide insights into expanding the scope of this method to include diverse functional groups beyond organoboronates.

What are the potential limitations or challenges in applying this SNV reaction to a broader range of substrates, and how could they be addressed?

One potential limitation in applying the SNV reaction to a broader range of substrates is the requirement for specific electronic and steric properties to facilitate the proposed strain-release mechanism. Substrates that do not possess the necessary characteristics may not undergo the desired stereospecific alkenylidene homologation efficiently. To address this challenge, researchers can explore the use of different metal catalysts or ligands that can modulate the reactivity of the substrates. Additionally, optimizing reaction conditions such as temperature, concentration, and reaction time can enhance the efficiency and scope of the SNV reaction. Furthermore, conducting thorough computational studies to understand the factors influencing the reactivity of different substrates can aid in overcoming limitations and expanding the applicability of this method to a broader range of molecules.

Given the unusual SN2-like concerted pathway proposed for this SNV reaction, what other types of organic transformations could potentially be developed based on similar strain-release mechanisms in metallated complexes?

The unusual SN2-like concerted pathway proposed for the SNV reaction opens up possibilities for developing other types of organic transformations based on similar strain-release mechanisms in metallated complexes. One potential transformation could involve the stereospecific alkenylation of electron-deficient substrates through a concerted nucleophilic substitution process. By leveraging the strain-release concept in metallated complexes, it may be possible to achieve selective and efficient alkenylation reactions on a variety of electron-deficient functional groups. Additionally, exploring the reactivity of different electrophiles towards metallated complexes under similar strain-release conditions could lead to the development of novel carbon-carbon bond-forming reactions with high stereoselectivity. Computational studies and experimental validation of these proposed transformations can provide valuable insights into the design of new synthetic methodologies based on strain-release mechanisms in metallated complexes.