Summary of the project
Stereoselective synthesis is a crucial aspect of modern organic chemistry, enabling the precise formation of specific stereoisomers in complex molecules. At the core of stereoselective synthesis lies the concept of reactive intermediates—transient species that are crucial in forming the desired stereoisomers. These intermediates (carbene, radical, carbocation) are typically short-lived, highly reactive and play a vital role in the mechanism and outcome of reactions. Understanding the formation, stability, and reactivity of these intermediates is essential for developing efficient synthetic routes with high chemo- and stereoselectivity.
Many existing methods for stereoselective synthesis rely on the rearrangements of reactive cationic intermediates. Because of the planar nature of carbocations, these rearrangements exhibit stereoselectivity primarily in cyclic systems, which act as “scaffolding” to impose specific geometric constraints. Obtaining stereochemically enriched acyclic compounds via cationic intermediates is more challenging due to the inherent flexibility of these systems, even though accessing these acyclic compounds is as crucial as accessing chiral cyclic compounds.
Neighboring group participation (NGP) is a fundamental concept in organic chemistry, where non-conjugated electrons interact with a reactive center to influence the course of the reaction. This interaction can stabilize the reaction intermediate, leading to changes in the reaction mechanism, rate, product distribution, and stereochemistry. A unique class of NGP is σ-bond participation, where a C–C bond donates its electrons to the reaction center. This participation results in unusual tetracoordinated carbocations known as “non-classical carbocations”. The formation of these non-classical carbocations represents some of the most intriguing carbocations, and despite decades of investigation, their reactivity remains not well understood and predictable, particularly for the control of stereochemistry in the formation of acyclic products. In unsubstituted cyclopropyl, cyclobutyl and homoallyl cationic systems, the structure of the cation is bicyclobutonium ion (BB). When substituents are introduced, there is another possible structure, called cyclopropylcarbinyl cation (CPC). Depending on the substituent and substitution pattern, the structure of the cation can be BB, CPC, or both can be in equilibrium. In electronically biased systems, the structure might also be a classical carbocation. Numerous studies have demonstrated the applications of these rearrangements in synthesis, providing diverse molecular frameworks. However, predicting the structure, particularly for polysubstituted systems in acyclic systems, remains an unsolved challenge.
These intermediates can enable rearrangements that alter the carbon backbone significantly. The study of their stereochemistry to provide acyclic molecular backbone has rarely been studied and is in its complete infancy. Indeed, the dynamic nature of these non-classical cations can lead to multiple stereoisomers. But, in contrast to classical planar trivalent cations, non-classical cations bear stereochemical information embedded within their tetracoordinated structure. Inspired by these central features, we set out to devise strategies to control reactivity and most importantly stereochemistry for non-classical carbocations.
To succeed in this undertaking, we must address several critical questions:
- Can we develop a predictive model based on substituents and substitution patterns that would allow for the formation of a single reactive non-classical carbocation intermediate? Can we use this model to design the synthesis of complex molecular skeletons as a single diastereomer?
- Can we perform the subsequent substitution with a complete control of the stereochemistry?
- Will this model enable us to selectively migrate a C–C bond though rearrangement at a distant position from the original carbocation and form a new center with complete stereocontrol? Can we achieve C–C bond migration at a quaternary carbon center to prepare regio-, diastereo- and enantiomerically enriched acyclic products with several adjacent stereocenters as unique isomers? How can C–C bond migration be performed under mild conditions that tolerate the presence of functional groups? How can we control the selectivity of C–C bond migration when multiple C–C bonds are present, ensuring only one bond is selectively activated? What would be the resulting stereochemistry?
- What types of nucleophiles would be compatible?
- Can we prepare new starting materials leading to the required stereodefined pattern of non-classical carbocations?
- Can we use these strategies to prepare polysubstituted fused small rings as single diastereo- and enantiomers?
- Could this approach become a general, reliable and fully predictable method in organic synthesis?
We recognize the complexity to answer these synthetic challenges. Successful implementation of these strategies could lead to the development of novel, selective, and efficient methods to create adjacent stereocenters.