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Reporting period: 2016-08-01 to 2018-07-31

The development of new chemical reactions allows to prepare substances with scientific relevance and useful properties more efficiently and in a selective manner. The ability to make carbon-based compounds holds a great importance in the synthesis of medicines, fragrances, polymers, materials, catalysts and the study of biological and physical properties. Among these compounds, chiral molecules represent an additional challenge. Chiral molecules are those which are non-superimposable on its mirror image. The mirror images of a chiral molecule are called enantiomers, and the chemical properties of each enantiomer of a given chiral molecule can be very different, therefore reactions that allow the preparation of one single enantiomer are of paramount importance.
Asymmetric carbon-carbon bond forming reactions generate single enantiomers of chiral molecules at the same time as the molecular framework is assembled and is therefore a very powerful strategy in organic synthesis. Two strategies for generating single enantiomer compounds using enantioselective catalysis have become widely embraced: the first generates a chiral product by a reaction which introduces asymmetry to a prochiral substrate. This prochiral approach has proven important in the development of catalytic asymmetric reactions, despite the rather limited availability of prochiral substrates when compared to chiral substrates. The second widely used approach is to start from a racemic mixture (this is a 1:1 mixture of the two enantiomers of a chiral molecule). Here the catalyst selectively reacts with one of the two enantiomers allowing differentiation (or resolution) of the enantiomers, but the yield is necessarily limited to 50%, as the undesired enantiomer remains as starting material.
An efficient variation of this second strategy is to couple enantiomer differentiation with interconversion of the enantiomers. This strategy allows yields over 50% from chiral starting materials while still producing highly enantiomerically enriched products. Despite the usefulness of this approach, it remains underdeveloped in contrast with the more traditional strategies mentioned above. Professor Fletcher research group has contributed to this field with the development of new dynamic kinetic asymmetric transformations (DYKATs) that employ racemic mixtures of cyclic allyl halides as electrophiles in combination with alkenes or boronic acids as nucleophiles to achieve enantiopure products in yields over 50%.
The overall objectives of this project were the expansion of the scope of the DYKAT processes previously developed by the group. Thus, examination of new nucleophiles that can be used in combination with racemic mixtures of allyl halides has been carried out. The use of biologically-relevant heterocyclic scaffolds as electrophiles was also studied in combination with the successful new nucleophiles. Additionally, the study of alternative DYKAT procedures that relay on the use of more abundant or stable starting materials has also been carried out.
The researcher explored multiple strategies with the aim of expanding the scope of DYKATs that use racemic mixtures of cyclic allyl chlorides as starting materials. The most fruitful strategy of those studied was the use of organosilanes as coupling partners, which allows an alternative procedure to the use of boronic acids previously developed by the group. Initial optimisation of the reaction conditions involved the test of several Rh(I) catalysts, ligands and additives. Once the optimal reaction conditions were defined, the study of the generality of the process was carried out. Thus, a variety of arylsiloxanes were tested in combination with 3-chlorocyclohex-1-ene giving rise to the corresponding allyl arenes in generally moderate yields but excellent enantioselectivities (92 to 99% of enantiomeric excess). Next, we decided to explore heterocyclic allyl chloride coupling partners. Interestingly, this methodology is compatible with dihydropyran and piperidine derivatives, affording the corresponding enantiopure products bearing a heterocyclic scaffold. This feature adds great value to the reaction. Indeed, the synthesis of piperidine derivatives holds a significant importance within chemistry as it is present in numerous natural alkaloids, pharmaceuticals and various synthetic substances with important properties. The number of asymmetric processes that use arylsiloxanes as coupling partners is scarce, and therefore this new reactivity represents a rare example of asymmetric Hiyama-type coupling.

The results obtained during the study of organosilicon coupling partners in DYKATs have been submitted for publication and the status is currently under review. Additionally, this findings were disseminated via poster presentation in the Gordon Research Conference in Stereochemistry that took place in the Salve Regina University, Rhode Island, from July the 22nd to the 27th.
Cross-coupling reactions occupy a privileged place among the tools to assemble carbon-based frameworks and Suzuki, Negishi, Heck and related reactions are established routine procedures. In general, the development of carbon-carbon bond forming cross-coupling reactions has mainly focused on the construction of Csp2–Csp2 bonds, while the formation of Csp3–Csp2 bonds is more elusive. The Fletcher group described Rh-catalyzed Suzuki-Miyaura type procedures where boronic acids are coupled to racemic cyclic allyl halides in a Csp3-Csp2 bond forming process with high levels of enantioinduction.

In this project, organosilanes were used as coupling partners instead of boronic acids, representing a new example of Hiyama-type coupling. The use of organosilicon coupling partners is attractive. Non-toxicity, stability and ease of handling are features that promise to make organosilanes useful in an array of synthetic applications. Moreover, along with studies of their reactivity and applications, novel approaches for the preparation of organosilanes is an area of active research. It should be also noted that asymmetric Hiyama-type procedures are scarce in the literature.

Thus, we have reported highly enantioselective Rh-catalyzed cross-couplings between arylsiloxanes and racemic cyclic allyl chlorides. This process represents a rare example of asymmetric Hiyama coupling, The method enables the preparation of valuable allyl arenes with uniformly high enantioselectivity (92->99% ee). Important heterocyclic scaffolds are compatible with this transformation, leading to highly enantioenriched dihydropyran and piperidine derivatives.