For many years, chemists have regarded the [1,2]-Wittig rearrangement as a tenacious deviation from the norm – a potent carbon–carbon bond-forming reaction thought to occur via erratic radical pairs and largely eluding precise catalytic management. However, a recent investigation reveals that it can actually be directed with precision, paving the way for enantioenriched tertiary alcohols.
The Wittig rearrangement is part of a larger category of reactions known as sigmatropic rearrangements, which are efficient processes that reorganize bonds through clearly defined transition states and are commonly employed in the construction of intricate molecules.
Among these, the [2,3]- and [1,2]-types hold particular significance. Yet while [2,3]-rearrangements manifest as relatively ‘well behaved,’ the [1,2] variant has historically resisted stereochemical oversight. ‘[1,2]-rearrangements are not allowed to occur in a concerted manner … making enantioselective variants scarce and particularly difficult,’ states Andrew Smith from the University of St Andrews.
Smith, alongside Matt Grayson from the University of Bath and their respective teams, has discovered a highly enantioselective pathway to [1,2]-Wittig products that avoids the traditionally accepted radical mechanism altogether. ‘[Initially, we] proposed a straightforward hypothesis: increasing steric hindrance at the end of an alkene would hinder [2,3]-rearrangement and promote [1,2]-rearrangement,’ remarks Smith. ‘Looking back, we couldn’t have been more mistaken and were astonished by the mechanism we unveiled.’
In contrast to the more recognized Wittig olefination, which yields alkenes, the Wittig rearrangement relocates a group from oxygen to carbon and frequently produces a tertiary alcohol featuring a new chiral center. As this reaction generally proceeds via highly unstable intermediates, controlling its three-dimensional outcome has long posed challenges.
Consequently, the innovative catalytic method transforms an unpredictable rearrangement into a dependable technique for establishing stereochemistry while generating a carbon–carbon bond. ‘To fully grasp the process, we depended on computational analysis, which even yielded unexpected findings,’ Smith notes.
‘Much of the experimental data collected by the team could align with either a radical or anionic mechanism for the fragmentation and recombination event. The most conclusive evidence came from our computational analysis, which found no indications of a radical pathway,’ Grayson adds.
The transformation occurs through a sophisticated reaction cascade: a chiral bifunctional iminophosphorane catalyst first facilitates a precise [2,3]-sigmatropic rearrangement, defining the molecule’s chirality. This is succeeded by a base-induced fragmentation–recombination step that transfers chirality with impressive accuracy, ultimately yielding the desired [1,2]-Wittig products in up to 97:3 enantiomeric ratio.
‘The authors present compelling mechanistic evidence that backs their claim,’ states Fernanda Duarte from the University of Oxford, who did not participate in the study. ‘This effort transcends a mere workaround. It signifies a conceptual broadening of chemists’ comprehension of rearrangement mechanisms, particularly concerning stereochemistry.’
Duarte contends that a deeper understanding of these rearrangements necessitates better integration of complementary strategies, including synthesis, kinetics, and computational methods, alongside the expert judgment required to link them. ‘Rearrangements are often filled with surprises, and comprehending them necessitates meticulous analysis,’ she notes. ‘In an age increasingly influenced by machine learning methods, this publication underscores the enduring importance of classical physical–organic reasoning and mechanistic tools. These “outliers” [and] surprising outcomes are what grant us access to new realms of chemical space and novel products.’